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Nuts and health in aging

Posted in Atherogenic Processes & Pathology, Cardiovascular Research, Chemical Biology and its relations to Metabolic Disease, Curation, Cytokines, Diabetes Mellitus, Disease Biology, Epigenetics and Cardiovascular Risks, Fatty acids, Gastroenterology, Human aging, Human Immune System in Health and in Disease, Immunology, Inflammasome, Lipid metabolism, Metabolism, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nutrition, Nutrition and Phytochemistry, Origins of Cardiovascular Disease, tagged chronic diseases, healthy diet, Metabolism, nuts, prevention on November 29, 2015| Leave a Comment »

Nuts and health in aging

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Nut consumption and age-related disease

Giuseppe Grosso, Ramon Estruch

MATURITAS · OCT 2015 http://dx.doi.org/10.1016/j.maturitas.2015.10.014

Current knowledge on the effects of nut consumption on human health has rapidly increased in recent years and it now appears that nuts may play a role in the prevention of chronic age-related diseases. Frequent nut consumption has been associated with better metabolic status, decreased body weight as well as lower body weight gain over time and thus reduce the risk of obesity. The effect of nuts on glucose metabolism, blood lipids, and blood pressure are still controversial. However, significant decreased cardiovascular risk has been reported in a number of observational and clinical intervention studies. Thus, findings from cohort studies show that increased nut consumption is associated with a reduced risk of cardiovascular disease and mortality (especially that due to cardiovascular-related causes). Similarly, nut consumption has been also associated with reduced risk of certain cancers, such as colorectal, endometrial, and pancreatic neoplasms. Evidence regarding nut consumption and neurological or psychiatric disorders is scarce, but a number of studies suggest significant protective effects against depression, mild cognitive disorders and Alzheimer’s disease. The underlying mechanisms appear to include antioxidant and anti-inflammatory actions, particularly related to their mono- and polyunsaturated fatty acids (MUFA and PUFA, as well as vitamin and polyphenol content. MUFA have been demonstrated to improve pancreatic beta-cell function and regulation of postprandial glycemia and insulin sensitivity. PUFA may act on the central nervous system protecting neuronal and cell-signaling function and maintenance. The fiber and mineral content of nuts may also confer health benefits. Nuts therefore show promise as useful adjuvants to prevent, delay or ameliorate a number of chronic conditions in older people. Their association with decreased mortality suggests a potential in reducing disease burden, including cardiovascular disease, cancer, and cognitive impairments.

Global life expectancy has increased from 65 years in 1990 to about 71 years in 2013 [1]. As life expectancy has increased, the number of healthy years lost due to disability has also risen in most countries, consistent with greater morbidity [2]. Reduction of mortality rates in developed countries has been associated with a shift towards more chronic non-communicable diseases [1]. Cardiovascular diseases (CVDs) and related risk factors, such as hypertension, diabetes mellitus, hypercholesterolemia, and obesity are the top causes of death globally, accounting for nearly one-third of all deaths worldwide [3]. Equally, the estimated incidence, mortality, and disability- adjusted life-years (DALYs) for cancer rose to 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs, with the highest impact of prostate and breast cancer in men and women, respectively [4]. Depression is a leading cause of disability worldwide (in terms of total years lost due to disability), especially in high-income countries, increasing from 15th to 11th rank (37% increase) and accounting for 18% of total DALYs (almost 100 million DALYs) [5]. Overall, the global rise in chronic non-communicable diseases is congruent with a similar rise in the elderly population. The proportion of people over the age of 60 is growing faster than any other age group and is estimated to double from about 11% to 22% within the next 50 years [6]. Public health efforts are needed to face this epidemiological and demographic transition, both improving the healthcare systems, as well as assuring a better health in older people. Accordingly, a preventive approach is crucial to dealing with an ageing population to reduce the burden of chronic disease.

In this context, lifestyle behaviors have demonstrated the highest impact for older adults in preventing and controlling the morbidity and mortality due to non- communicable diseases [7]. Unhealthy behaviors, such as unbalanced dietary patterns, lack of physical activity and smoking, play a central role in increasing both cardiovascular and cancer risk [7]. Equally, social isolation and depression in later life may boost health decline and significantly contribute to mortality risk [8]. The role of diet in prevention of disability and death is a well-established factor, which has an even more important role in geriatric populations. Research has focused on the effect of both single foods and whole dietary patterns on a number of health outcomes, including mortality, cardiovascular disease (CVD), cancer and mental health disorders (such as cognitive decline and depression) [9-13]. Plantbased dietary patterns demonstrate the most convincing evidence in preventing chronic non-communicable diseases [14-17]. Among the main components (including fruit and vegetables, legumes and cereals), only lately has attention focused on foods such as nuts. Knowledge on the effect of nut consumption on human health has increased rapidly in recent years. The aim of this narrative review is to examine recent evidence regarding the role of nut consumption in preventing chronic disease in older people.

Tree nuts are dry fruits with an edible seed and a hard shell. The most popular tree nuts are almonds (Prunus amigdalis), hazelnuts (Corylus avellana), walnuts (Juglans regia), pistachios (Pistachia vera), cashews (Anacardium occidentale), pecans (Carya illinoiensis), pine nuts (Pinus pinea), macadamias (Macadamia integrifolia), Brazil nuts (Bertholletia excelsa), and chestnuts (Castanea sativa). When considering the “nut” group, researchers also include peanuts (Arachis hypogea), which technically are groundnuts. Nuts are nutrient dense foods, rich in proteins, fats (mainly unsaturated fatty acids), fiber, vitamins, minerals, as well as a number of phytochemicals, such as phytosterols and polyphenols [18]. Proteins account for about 10-25% of energy, including individual aminoacids, such as L-arginine, which is involved in the production of nitric oxide (NO), an endogenous vasodilatator [19].

The fatty acids composition of nuts involves saturated fats for 415% and unsaturated fatty acids for 30-60% of the content. Unsaturated fatty acids are different depending on the nut type, including monounsaturated fatty acids (MUFA, such as oleic acid in most of nuts, whereas polyunsaturated fatty acids (PUFA, such as alpha-linolenic acid) in pine nuts and walnuts [20]. Also fiber content is similar among most nut types (about 10%), although pine nuts and cashews hold the least content. Vitamins contained in nuts are group B vitamins, such as B6 (involved in many aspects of macronutrient metabolism) and folate (necessary for normal cellular function, DNA synthesis and metabolism, and homocysteine detoxification), as well as tocopherols, involved in anti-oxidant mechanisms [21]. Among minerals contained in vegetables, nuts have an optimal content in calcium, magnesium, and potassium, with an extremely low amount of sodium, which is implicated on a number of pathological conditions, such as bone demineralization, hypertension and insulin resistance[22]. Nuts are also rich in phytosterols, non-nutritive components of certain plant-foods that exert both structural (at cellular membrane phospholipids level) and hormonal (estrogen-like) activities [23]. Finally, nuts have been demonstrated to be a rich source of polyphenols, which account for a key role in their antioxidant and anti-inflammatory effects.

Metabolic disorders are mainly characterized by obesity, hypertension, dyslipidemia, and hyperglycemia/ hyperinsulinemia/type-2 diabetes, all of which act synergistically to increase morbidity and mortality of aging population.

Obesity Increasing high carbohydrate and fat food intake in the last decades has contributed significantly to the rise in metabolic disorders. Nuts are energy-dense foods that have been thought to be positively associated with increased body mass index (BMI). As calorie-dense foods, nuts may contain 160–200 calories per ounce. The recommendation from the American Heart Association to consume 5 servings per week (with an average recommended serving size of 28 g) corresponds to a net increase of 800–1000 calories per week, which may cause weight gain. However, an inverse relation between the frequency of nut consumption and BMI has been observed in large cohort studies [24]. Pooling the baseline observations of BMI by category of nut consumption in 5 cohort studies found a significant decreasing trend in BMI values with increasing nut intake [24]. While the evidence regarding nut consumption and obesity is limited, findings so far are encouraging [25, 26]. When the association between nut consumption and body weight has been evaluated longitudinally over time, nut intake was associated with a slightly lower risk of weight gain and obesity [25]. In the Nurses’ Health Study II (NHS II), women who eat nuts ≥2 times per week had slightly less weight gain (5.04 kg) than did women who rarely ate nuts (5.55 kg) and marginally significant 23% lower risk of obesity after 9-year follow-up [25]. Further evaluation of the NHS II data and the Physicians’ Health Study (PHS) comprising a total of 120,877 US women and men and followed up to 20 years revealed that 4-y weight change was inversely associated with a 1-serving increment in the intake of nuts (20.26 kg) [27]. In the “Seguimiento Universidad de Navarra” (SUN) cohort study, a significant decreased weight change has been observed over a period of 6 years [26]. After adjustment for potential confounding factors the analysis was no longer significant, but overall no weight gain associated with >2 servings per week of nuts has been observed. Finally, when considering the role of the whole diet on body weight, a meta-analysis of 31 clinical trials led to the conclusion of a null effect of nut intake on body weight, BMI, and waist circumference [28].

Glucose metabolism and type-2 diabetes The association between nut consumption and risk of type-2 diabetes in prospective cohort studies is controversial [29-32]. A pooled analysis relied on the examination of five large cohorts, including the NHS, the Shanghai Women’s Health Study, the Iowa Women’s Health Study, and the PHS, and two European studies conducted in Spain (the PREDIMED trial) and Finland including a total of more than 230,000 participants and 13,000 cases, respectively. Consumption of 4 servings per week was associated with 13% reduced risk of type-2 diabetes without effect modification by age [29]. In contrast, other pooled analyses showed non-significant reduction of risk for increased intakes of nuts, underlying that the inverse association between the consumption of nuts and diabetes was attenuated after adjustment for confounding factors, including BMI [30]. However, results from experimental studies showed promising results. Thus, nut consumption has been demonstrated to exert beneficial metabolic effects due to their action on post-prandial glycemia an insulin sensitivity. A number of RCTs have demonstrated positive effects of nut consumption on post-prandial glycemia in healthy individuals [33-38]. Moreover, a meta-analysis of RCTs on the effects of nut intake on glycemic control in diabetic individuals including 12 trials and a total of 450 participants showed that diets with an emphasis on nuts (median dose = 56 g/d) significantly lowered HbA1c (Mean Difference [MD] : -0.07%; 95% confidence interval [CI]: -0.10, -0.03%; P = 0.0003) and fasting glucose (MD : -0.15 mmol/L; 95% CI: -0.27, -0.02 mmol/L; P = 0.03) compared with control diets [39]. No significant treatment effects were observed for fasting insulin and homeostatic model assessment (HOMA-IR), despite the direction of effect favoring diet regimens including nuts.

Blood lipids and hypertension Hypertension and dyslipidemia are major risk factors for CVD. Diet alone has a predominant role in blood pressure and plasma lipid homeostasis. One systematic review [40] and 3 pooled quantitative analyses of RCTs [41-43] evaluated the effects of nut consumption on lipid profiles. A general agreement was relevant on certain markers, as daily consumption of nuts (mean = 67 g/d) induced a pooled reduction of total cholesterol concentration (10.9 mg/dL [5.1% change]), low-density lipoprotein cholesterol concentration (LDL-C) (10.2 mg/dL [7.4% change]), ratio of LDL-C to high-density lipoprotein cholesterol concentration (HDL-C) (0.22 [8.3% change]), and ratio of total cholesterol concentration to HDL-C (0.24 [5.6% change]) (P <0.001 for all) [42]. All meta-analyses showed no significant effects of nut (including walnut) consumption on HDL cholesterol or triglyceride concentrations in healthy individuals [41], although reduced plasma triglyceride levels were found in individuals with hypertriglyceridemia [42]. Interestingly, the effects of nut consumption were dose related, and different types of nuts had similar effects on blood lipid concentrations.

There is only limited evidence from observational studies to suggest that nuts have a protective role on blood pressure. A pooled analysis of prospective cohort studies on nut consumption and hypertension reported a decreased risk associated with increased intake of nuts [32]. Specifically, only a limited number of cohort studies have been conducted exploring the association between nut consumption and hypertension (n = 3), but overall reporting an 8% reduced risk of hypertension for individuals consuming >2 servings per week (Risk Ratio [RR] = 0.92, 95% CI: 0.87-0.97) compared with never/rare consumers, whereas consumption of nuts at one serving per week had similar risk estimates (RR = 0.97, 95% CI: 0.83, 1.13) [32]. These findings are consistent with results obtained in a pooled analysis of 21 experimental studies reporting the effect of consuming single or mixed nuts (in doses ranging from 30 to 100 g/d) on systolic (SBP) and diastolic blood pressure (DBP) [44]. A pooled analysis found a significant reduction in SBP in participants without type2 diabetes [MD: -1.29 mmHg; 95% CI: -2.35, -0.22; P = 0.02] and DBP (MD: -1.19; 95% CI: -2.35, -0.03; P = 0.04), whereas subgroup analyses of different nut types showed that pistachios, but not other nuts, significantly reduced SBP (MD: -1.82; 95% CI: -2.97, -0.67; P = 0.002) and SBP (MD: -0.80; 95% CI: -1.43, -0.17; P = 0.01) [44].

Nut consumption and CVD risk Clustering of metabolic risk factors occurs in most obese individuals, greatly increasing risk of CVD. The association between nut consumption and CVD incidence [29-31] and mortality [24] has been explored in several pooled analyses of prospective studies. The overall risk calculated for CVD on a total of 8,862 cases was reduced by 29% for individuals consuming 7 servings per week (RR = 0.71, 95% CI: 0.59, 0.85) [30]. A meta-analysis including 9 studies on coronary artery disease (CAD) including 179,885 individuals and 7,236 cases, reporting that 1-serving/day increment would reduce risk of CAD of about 20% (RR = 0.81, 95% CI: 0.72, 0.91) [31]. Similar risk estimates were calculated for ischemic heart disease (IHD), with a comprehensive reduced risk of about 25-30% associated with a daily intake of nuts [29, 30]. Findings from 4 prospective studies have been pooled to estimate the association between nut consumption and risk of stroke, and a non-significant/borderline reduced risk was found [29-31, 45]. CVD mortality was explored in a recent meta-analysis including a total of 354,933 participants, 44,636 cumulative incident deaths, and 3,746,534 cumulative person-years [24]. One serving of nuts per week and per day resulted in decreased risk of CVD mortality (RR = 0.93, 95% CI: 0.88, 0.99 and RR =0.61, 95% CI: 0.42, 0.91, respectively], primarily driven by decreased coronary artery disease (CAD) deaths rather than stroke deaths [24]. Overall, all pooled analyses demonstrated a significant association between nut consumption and cardiovascular health. However, it has been argued that nut consumption was consistently associated with healthier background characteristics reflecting overall healthier lifestyle choices that eventually lead to decreased CVD mortality risk.

Nut consumption and cancer risk Cancer is one of the leading causes of death in the elderly population. After the evaluation of the impact on cancer burden of food and nutrients, it has been concluded that up to one third of malignancies may be prevented by healthy lifestyle choices. Fruit and vegetable intake has been the focus of major attention, but studies on nut consumption and cancer are scarce. A recent metaanalysis pooled together findings of observational studies on cancer incidence, including a total of 16 cohort and 20 casecontrol studies comprising 30,708 cases, compared the highest category of nut consumption with the lowest category and found a lower risk of any cancer of 25% (RR = 0.85, 95% CI: 0.86, 0.95) [46]. When the analysis was conducted by cancer site, highest consumption of nuts was associated with decreased risk of colorectal (RR = 0.76, 95% CI: 0.61, 0.96), endometrial (RR = 0.58, 95% CI: 0.43, 0.79), and pancreatic cancer (RR = 0.71, 95% CI: 0.51, 0.99), with only one cohort study was conducted on the last [46]. The potential protective effects of nut consumption on cancer outcomes was supported also by pooled analysis of 3 cohort studies [comprising the PREDIMED, the NHS, the HPS, and the Health Professionals Follow-Up Study (HPFS) cohorts] showing a decreased risk of cancer death for individuals consuming 3-5 servings of nuts per week compared with never eaters (RR = 0.86, 95% CI: 0.75, 0.98) [24]. The analysis was recently updated by including results from the Netherlands Cohort Study reaching a total of 14,340 deaths out of 247,030 men and women observed, confirming previous results with no evidence of between-study heterogeneity (RR = 0.85, 95% CI: 0.77, 0.93) [47]. However, a dose- response relation showed the non-linearity of the association, suggesting that only moderate daily consumption up to 5 g reduced risk of cancer mortality, and extra increased intakes were associated with no further decreased risk.

Nut consumption and affective/cognitive disorders Age-related cognitive decline is one of the most detrimental health problems in older people. Cognitive decline is a paraphysiological process of aging, but timing and severity of onset has been demonstrated to be affected by modifiable lifestyle factors, including diet. In fact, the nature of the age- related conditions leading to a mild cognitive impairment (MCI) differs by inflammation-related chronic neurodegenerative diseases, such as dementia, Alzheimer’s disease, Parkinson’s disease and depression. Evidence restricted to nut consumption alone is scarce, but a number of studies have been conducted on dietary patterns including nuts as a major component. A pooled analysis synthesizing findings of studies examining the association between adherence to a traditional Mediterranean diet and risk of depression (n = 9), cognitive decline (n = 8), and Parkinson’s disease (n = 1) showed a reduction of risk of depression (RR = 0.68, 95% CI: 0.54, 0.86) and cognitive impairment (RR = 0.60, 95% CI: 0.43, 0.83) in individuals with increased dietary adherence [10].

The study that first found a decreased risk of Alzheimer’s disease in individuals highly adherent to the Mediterranean diet was conducted in over 2,000 individuals in the Washington/Hamilton Heights-Inwood Columbia Aging Project (WHICAP), a cohort of non-demented elders aged 65 and older living in a multi-ethnic community of Northern Manhattan in the US (Hazard Ratio [HR] = 0.91, 95% CI: 0.83, 0.98) [48]. These results have been replicated in further studies on the Mediterranean diet, however nut consumption was not documented [49, 50]. A number of observational studies also demonstrated a significant association between this dietary pattern and a range of other cognitive outcomes, including slower global cognitive decline [51]. However, evidence from experimental studies is limited to the PREDIMED trial, providing interesting insights on the association between the Mediterranean diet supplemented with mixed nuts and both depression and cognitive outcomes. Regarding depression, the nutritional intervention with a Mediterranean diet supplemented with nuts showed a lower risk of about 40% in participants with type-2 diabetes (RR = 0.59, 95% CI: 0.36, 0.98) compared with the control diet [52]. However the effect was not significant in the whole cohort overall [52]. Regarding cognitive outcomes after a mean follow-up of 4.1 years, findings from the same trial showed significant improvements in memory and global cognition tests for individuals allocated to the Mediterranean diet supplemented with nuts [adjusted differences: -0.09 (95% CI: -0.05, 0.23), P = 0.04 and -0.05 (95% CI: -0.27, 0.18), P = 0.04, respectively], compared to control group, showing that Mediterranean diet plus mixed nuts is associated with improved cognitive function [53].

Potential mechanisms of protection of nut consumption Despite the exact mechanisms by which nuts may ameliorate human health being largely unknown, new evidence has allowed us to start to better understand the protection of some high-fat, vegetable, energy-dense foods such as nuts. Non- communicable disease burden related with nutritional habits is mainly secondary to exaggerated intakes of refined sugars and saturated fats, such as processed and fast- foods. Nuts provide a number of nutrient and non-nutrient compounds and it is only recently that scientists have tried to examine their effects on metabolic pathways.

Metabolic and cardiovascular protection With special regard to body weight and their potential effects in decreasing the risk of obesity (or weight gain, in general), nuts may induce satiation (reduction in the total amount of food eaten in a single meal) and satiety (reduction in the frequency of meals) due to their content in fibers and proteins, which are associated with increased release of glucagon-like protein 1 (GLP-1) and cholecystokinin (CCK), gastrointestinal hormones with satiety effects [54, 55]. The content in fiber of nuts may also increase thermogenesis and resting energy expenditure, and reduce post- prandial changes of glucose, thus ameliorating inflammation and insulin resistance. Moreover, the specific content profile of MUFA and PUFA provides readily oxidized fats than saturated or trans fatty acids, leading to reduced fat accumulation [56, 57]. The beneficial effects of nuts toward glucose metabolism may be provided by their MUFA content that improves the efficiency of pancreatic beta-cell function by enhancing the secretion of GLP1, which in turn helps the regulation of postprandial glycemia and insulin sensitivity [58]. MUFA and PUFA are also able to reduce serum concentrations of the vasoconstrictor thromboxane 2, which might influence blood pressure regulation. Together with polyphenols and anti-oxidant vitamins, nuts may also ameliorate inflammatory status at the vascular level, reducing circulating levels of soluble cellular adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, which are released from the activated endothelium and circulating monocytes [59]. Moreover, nuts may improve vascular reactivity due to their content in L-arginine, which is a potent precursor of the endogenous vasodilator nitric oxide. Nuts content in microelements is characterized by a mixture that may exert a direct effect in modulating blood pressure, including low content of sodium and richness in magnesium, potassium and calcium, which may interact to beneficially influence blood pressure
Despite the exact mechanisms by which nuts may ameliorate human health being largely unknown, new evidence has allowed us to start to better understand the protection of some high-fat, vegetable, energy-dense foods such as nuts. Non- communicable disease burden related with nutritional habits is mainly secondary to exaggerated intakes of refined sugars and saturated fats, such as processed and fast- foods. Nuts provide a number of nutrient and non-nutrient compounds and it is only recently that scientists have tried to examine their effects on metabolic pathways.

Cancer protection The potential mechanisms of action of nuts that may intervene in the prevention of cancer have not been totally elucidated. Numerous hypotheses have been proposed on the basis of basic research exploring the antioxidant and anti-inflammatory compounds characterizing nuts [61]. Vitamin E can regulate cell differentiation and proliferation, whereas polyphenols (particularly flavonoids such as quercetin and stilbenes such as resveratrol) have been shown to inhibit chemically-induced carcinogenesis [62]. Polyphenols may regulate the inflammatory response and immunological activity by acting on the formation of the prostaglandins and pro-inflammatory cytokines, which may be an important mechanism involved in a number of cancers, including colorectal, gastric, cervical and pancreatic neoplasms [62]. Among other compounds contained in nuts, dietary fiber may exert protective effects toward certain cancers (including, but not limited to colorectal cancer) by the aforementioned metabolic effects as well as increasing the volume of feces and anaerobic fermentation, and reducing the length of intestinal transit. As a result, the intestinal mucosa is exposed to carcinogens for a reduced time and the carcinogens in the colon are diluted [62]. Finally, there is no specific pathway demonstrating the protective effect of PUFA intake against cancer, but their interference with cytokines and prostaglandin metabolism may inhibit a state of chronic inflammation that may increase cancer risk [63].

Cognitive aging and neuro-protection There is no universal mechanism of action for nuts with regard to age-related conditions. A number of systemic biological conditions, such as oxidative stress, inflammation, and reduced cerebral blood flow have been considered as key factors in the pathogenesis of both normal cognitive ageing and chronic neurodegenerative disease [64]. Nuts, alone or as part of healthy dietary patterns, may exert beneficial effects due to their richness in antioxidants, including vitamins, polyphenols and unsaturated fatty acids, that may be protective against the development of cognitive decline and depression [65, 66]. Both animal studies and experimental clinical trials demonstrated vascular benefits of nuts, including the aforementioned lowering of inflammatory markers and improved endothelial function, which all appear to contribute to improved cognitive function [67]. The antioxidant action may affect the physiology of the ageing brain directly, by protecting neuronal and cell-signaling function and maintenance. Moreover, certain compounds contained in nuts may directly interact with the physiology and functioning of the brain. For instance, walnuts are largely composed of PUFA, especially ALA, which have been suggested to induce structural change in brain areas associated with affective experience [66]. Moreover, PUFA have been associated with improved symptoms in depressed patients, suggesting an active role in the underlying pathophysiological mechanisms [68]. Thus, the mechanisms of action of nut consumption on age-related cognitive and depressive disorders are complex, involving direct effects on brain physiology at the neuronal and cellular level and indirect effects by influencing inflammation.

Summary From an epidemiological point of view, nut eaters have been associated with overall healthier lifestyle habits, such as increased physical activity, lower prevalence of smoking, and increased consumption of fruits and vegetables [24]. These variables represent strong confounding factors in determining the effects of nuts alone on human health and final conclusions cannot be drawn. Nevertheless, results from clinical trials are encouraging. Nuts show promise as useful adjuvants to prevent, delay or ameliorate a number of chronic conditions in older people.

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Obesity Pharmaceutics

Posted in Curation, Human aging, Metabolism, Nutrition, Nutrition Disorders, Nutritional Supplements: Atherogenesis, Obesity, tagged disease/medicine and appetite, Drug development, drug toxicity, FDA, Obesity, regulation on November 19, 2015| Leave a Comment »

Obesity Pharmaceutics

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Battling the Bulge

Weight-loss drugs that target newly characterized obesity-related receptors and pathways could finally offer truly effective fat control.

By Bob Grant | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44322/title/Battling-the-Bulge/

http://www.the-scientist.com/November2015/NovBioBiz2_640px.jpg

Several years ago, antiobesity drug development was not looking so hot. In 2007, Sanofi-Aventis failed to win US Food and Drug Administration (FDA) approval for rimonabant—a pill that successfully helped people shed pounds—because the drug carried risks of depression and suicidal thoughts. Then, in 2008, Merck pulled the plug on its Phase 3 trials of taranabant because it also engendered suicidal thoughts and neurological effects in some participants. And a decade before those late-stage disappointments, a couple of FDA-approved weight-loss drugs were making headlines for carrying dangerous side effects. In 1997, the FDA pulled the obesity medications fenfluramine (of the wildly popular fen-phen drug combination) and dexfenfluramine (Redux) off the market after research turned up evidence of heart valve damage in people taking the drugs.

By 2009, Big Pharma was backing out of the weight-loss market, with Merck and Pfizer abandoning their programs to develop drugs similar to rimonabant and taranabant, which block cannabinoid receptors in the brain. Although the antiobesity drug market was big—according to CDC estimates, about 35 percent of adults in the U.S. are obese—a blockbuster weight-loss pill that didn’t have serious side effects was proving elusive.

But a few firms, including several small biotechs, decided to stick with it. “Some of the prior experience with drugs on the market, like fen-phen and Redux, have likely led large pharma to view the therapeutic space with some conservatism,” says Preston Klassen, executive vice president and head of global development at Orexigen Therapeutics, a small, California-based firm. “And generally, when you have that situation, smaller companies will step into that void when the science makes sense.” And their perseverance is starting to pay off. After a years-long drought in approvals for antiobesity medications, in the past few years the FDA has approved four new drugs specifically for general obesity: Belviq and Qsymia in 2012, and Contrave and Saxenda in late 2014. Three of these four were developed by small companies whose success hinges on one or a few compounds aimed directly at treating general obesity.

The recent burst of antiobesity drug approvals reflects an evolving appreciation for the molecular intricacies of this multifaceted, chronic disease. Today’s antiobesity drugs—including the four recent approvals and several more in development—have traded the blunt cudgel of appetite suppression for more precise targeting of pathways known to play roles in obesity. “With our understanding of the complex biology of obesity and all of the different molecules and receptors involved in the process, we’re much better able to target those molecules and receptors,” says Arya Sharma, chair in obesity research and management at the University of Alberta in Canada. “These are very specific agents that are designed for very specific actions. There is renewed enthusiasm in this field.”

Looking to combos

In the mid-20th century, the FDA approved several weight-loss drugs, starting with the appetite suppressant desoxyephedrine (methamphetamine hydrochloride) in 1947. Like the other appetite-suppressing drugs the FDA later approved through the 1950s and ’60s, desoxyephedrine accomplished short-term weight loss, but the transient benefit did not justify the side effects of long-term use, such as addiction, psychosis, and violent behavior. In 1973, as the nation voiced concern about the overuse of amphetamines, the FDA decreed that all obesity drugs were approved only for short-term use. The most recently approved obesity drugs, on the other hand, all have the FDA’s okay for long-term weight management.

Three of the newly approved drugs, Contrave, Belviq, and Qsymia, also aim to suppress appetite, and like many previous weight-loss therapies, all do so by targeting the hypothalamus, the brain region thought to be the seat of appetite control. Although the precise mechanism of Belviq, which is manufactured by San Diego–based Arena Pharmaceuticals, is unknown, researchers think that the key is its activation of serotonin-binding 5-HT2C receptors in proopiomelanocortin (POMC) neurons in the hypothalamus. When activated, these neurons reduce appetite and increase energy expenditure, according to Orexigen’s Klassen. His company’s Contrave also activates POMC neurons in the hypothalamus, while at the same time inhibiting opioid receptors, which would otherwise work to shut down POMC neuron firing, in the brain’s mesolimbic reward pathway. Contrave achieves this one-two punch because it is a combination therapy, incorporating two different compounds into a single weight-loss pill.

“The concept of a silver or magic bullet whereby one drug meets all of the needs within the obesity space has thus far proven to be inadequate,” says Klassen. “Right now I think the predominant opinion is that combination therapy is an appropriate way to go.”

Vivus’s Qsymia is also a combination drug, composed of phentermine—the other half of fen-phen and an activator of a G protein–coupled receptor called TAAR1—and an extended-release form of topiramate, an anticonvulsant with weight-loss side effects. Novo Nordisk—one of the few Big Pharma firms that stayed in the obesity game as others fled—is also turning its attention to combo therapies, testing its pipeline of investigational weight-loss compounds with Saxenda, its recently approved medicine that mimics glucagon peptide-1 (GLP-1), an appetite and calorie-intake regulator in the brain. “You need to combine at least two molecules to get the optimum effect,” says Novo Nordisk executive vice president and chief scientific officer Mads Krogsgaard Thomsen. The company has five other weight-loss compounds in development, and “we’re actually combining Saxenda with all of these new molecules,” he adds.

The University of Alberta’s Sharma agrees that combination therapies are a smart approach for attacking the multilayered mechanisms at play in obesity. “You’re dealing with a system that is very complex and very redundant. When you block one, other molecules or other parallel systems kick in,” he says. “My prediction for the future is that in order to get good results, one will have to move toward combinations . . . of more-specific and more-novel agents.”

On the horizon

On the heels of the recent FDA approvals, several new compounds with novel mechanisms of action are making their way through the drug-development pipeline. While most antiobesity drugs to date have aimed to suppress appetite by targeting brain regions involved in feelings of hunger and satiety, Boston-based Zafgen (for which Sharma serves as a paid advisor) is going after methionine aminopeptidase 2 (MetAP2) receptors in the liver and adipose tissue. “We’ve been one of the first ones to show that there is a significant and major weight-regulation center that the body has that exists outside the hypothalamus,” says Zafgen chief medical officer Dennis Kim. “Our drug [beloranib] is tapping into that mechanism.”

Zafgen researchers are investigating beloranib’s mechanism of action in patients that became very obese after their hypothalamus was damaged or removed as a result of craniopharyngioma, a type of brain cancer. “In about half of these cases, patients wake up hungry after surgery and it’s unrelenting, and they become morbidly obese very rapidly,” Kim says. Because the hypothalamus is damaged or missing, antiobesity drugs that target this brain region are ineffective. But beloranib “works just as well in these patients compared to patients with intact hypothalamus,” Kim says. As a result, beloranib may work in isolation without the need to combine different compounds, he adds. “If you can target a nodal point that’s much more upstream of simple circuitry-controlled hunger in the hypothalamus, you have the potential to reset the entire system.”

Meanwhile, another Boston-based firm, Rhythm Pharmaceuticals, is conducting clinical trials on obese patients with rare genetic disorders that compromise the melanocortin-4 (MC4) pathway, known to be involved in body weight regulation. Rhythm’s setmelanotide (RM-493) is a first-in-class drug that activates the MC4 pathway. And several companies, including the Japanese pharma firm Shionogi, are developing compounds that block the receptor of a neurotransmitter called neuropeptide Y, which plays a role in appetite stimulation and meal initiation.

Other new antiobesity targets include cyclic nucleotides, second messengers in signaling cascades such as the 3′-5′-cyclic guanosine monophosphate pathway, which conveys feelings of satiety and ramps up thermogenesis; amylin, a peptide hormone that slows gastric emptying and promotes satiety; ghrelin, a gut hormone that stimulates food intake; and a handful of pathways that affect nutrient absorption and metabolism. As more of obesity’s molecular complexities are sorted out, even more new drug targets will present themselves.

“I think we are on the verge of understanding obesity and the mechanisms underlying obesity,” says Novo Nordisk’s Thomsen. “That means that there is going to be a lot of good news for obesity going forward.”

WEIGHT-LOSS DRUG APPROVAL

© ISTOCK.COM/QUISP65Getting a weight-loss treatment approved by the FDA is a little different than the regulatory path taken by other drugs. To earn approval, companies must demonstrate that their drugs afford at least a 5 percent reduction in body weight over a year. And after a therapy reaches the market, companies have to conduct more research, specifically, into the drugs’ safety. Contrave, for example, which was approved in September 2014, is currently subject to rigorous post-marketing surveillance concerning evidence that the drug may lead to suicidal thoughts and behaviors. Other recently approved antiobesity drugs are under similar surveillance regimens.

The FDA also requires companies to test some approved weight-loss drugs specifically for their cardiovascular side effects. “Serious safety concerns have arisen with several obesity drugs in the past, which have informed our approach to drug development,” FDA spokesperson Eric Pahon wrote in an email to The Scientist. “All drugs approved for chronic weight management since 2012 have either had a cardiovascular outcome trial (CVOT) underway at the time of approval or have been required to initiate a CVOT as a post-marketing requirement.”

This additional testing, however, may scare off some drug developers from entering the antiobesity arena, Vivus spokesperson Dana Shinbaum wrote in an email to The Scientist. “The hurdles remain high . . . [and] may discourage innovation in this area.”

But even with the significant regulatory hurdles, it’s tough to deny the potential that exists in the antiobesity drug market. “We view obesity as one of the few remaining untapped therapeutic areas within primary care,” says Preston Klassen of Orexigen Therapeutics. “We think it’s tremendously important from a medical perspective, and we think it’s been well documented that even small reductions in body weight have meaningful and sustained impact on improved health.”

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Nutrition Plan

Posted in Nutrition, tagged good meal plans, healthy eating on November 18, 2015| Leave a Comment »

Nutrition Plan

Curator: Larry H. Bernstein, MD, FCAP

This Is What A Perfect Day Of Eating Looks Like

By LAUREN GELMAN

Raise your hand if you wish a nutritionist would tell you exactly what to eat and when to look and feel great all day long. Yeah, we thought so—that’s why we tapped three experts who counsel real women on the simple secrets of smarter meal planning.

1) Have a meal or small snack every 3 to 4 hours. This fuels your metabolism and helps prevent binges and blood sugar crashes.2) Combine protein (meat, fish, beans, nuts, eggs, dairy) and fiber (whole grains, fruits, vegetables) at every meal. When eaten together, these foods take longer to digest than simpler carbohydrates, so you stay fuller, longer.3) Get up, move around, and drink water often. This daily meal plan has a wide range of calories (from about 1,550 to 2,100); if you’re active you can go toward the higher end of the range.

Finally, remember that even the “perfect day” isn’t perfect if you eat the same thing over and over again. Use the principles outlined here to mix and match your own delicious, healthy meals.

Frank Sagliano

unfortunately most of our food stuff is nutrient void, the recommendations have been based on information from the 50’s . Read Hidden Hunger for validation . I have also been in agriculture for 40 years and have witnessed the change to corporate agriculture from quality to quantity . I can help aminos are the most important 75% of the human body dry weight , vitamins and minerals 1.5% . With age our bodies do not produce enough of endogenous aminos and exogenous are from the foods . They are heat sensitive ..

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Adenosine Receptor Agonist Increases Plasma Homocysteine

Posted in Biochemical pathways, Drug Toxicity, Gene Regulation, Genome Biology, Genomics Pharmacy, Human aging, Metabolism, Metabolomics, Micronutrients, Nutrigenomics, Nutrition, Nutrition and Phytochemistry, Nutrition Disorders, Pharmaceutical Analytics, Pharmaceutical Discovery, Pharmacologic toxicities, tagged 5’-N-Ethylcarboxamide-Adenosine, Adenosine, Glutathione, homocysteine on November 17, 2015| Leave a Comment »

Adenosine Receptor Agonist Increases Plasma Homocysteine

Larry H. Bernstein, MD, FCAP, Curator

LPBI

The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases

Spring Zhou Editor at Scientific Research Publishing

I would like to share this paper with you. Any comments on this article are welcome.

An increase in total homocysteine (Hcy) levels (protein-bound and free Hcy in the serum) has been identified as a risk factor for vascular diseases. Hcy is a product of the methionine cycle and is a precursor of glutathione in the transsulfuration pathway. The methionine cycle mainly occurs in the liver, with Hcy being exported out of the liver and subsequently bound to serum proteins. When the non-specific adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA; 0.1 or 0.3 mg/kg body weight) was intraperitoneally administered to mice that had been fasted for 16 h, total Hcy levels in the serum significantly increased 1 h after its administration. The NECA treatment may have inhibited transsulfuration because glutathione levels were significantly decreased in the liver. After the intraperitoneal administration of a high dose of NECA (0.3 mg/kg body weight), elevations in total Hcy levels in the serum continued for up to 10 h. The mRNA expression of methionine metabolic enzymes in the liver was significantly reduced 6 h after the administration of NECA. NECA-induced elevations in total serum Hcy levels may be maintained in the long term through the attenuated expression of methionine metabolic enzymes.

Comments:

Is level of protein consumption a factor?
Is reliance on plant food products a factor?
What are the levels of transthyretin?
Is there a concomitant decrease in vitamin A or vitamin D?

The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases

Shigeko Fujimoto Sakata^*, Koichi Matsuda, Yoko Horikawa, Yasuto Sasaki Faculty of Nutrition, Kobe Gakuin University, Kobe, Japan.

http://www.scirp.org/journal/PaperInformation.aspx DOI: 10.4236/pp.2015.610048

Cite this paper

Sakata, S. , Matsuda, K. , Horikawa, Y. and Sasaki, Y. (2015) The Adenosine Receptor Agonist 5’-N-Ethylcarboxamide-Adenosine Increases Mouse Serum Total Homocysteine Levels, Which Is a Risk Factor for Cardiovascular Diseases. Pharmacology & Pharmacy, 6, 461-470. doi: 10.4236/pp.2015.610048.

An increase in total serum homocysteine levels (total Hcy: serum protein-bound and free Hcy) has been identified as a risk factor for cardiovascular disease [1] [2] and liver fibrosis [3]. The normal range of total Hcy in adults is typically 5 – 15 μM, with the mean level being approximately 10 μM [2]. Plasma Hcy concentrations were previously found to be strongly associated with the presence and number of small infarctions, or infarction of the putamen in elderly diabetic patients [4]. High levels of Hcy have been shown to induce endoplasmic reticulum (ER) stress and increase the production of reactive oxygen species (ROS) [5]. Hcy has strong reducibility and modifies disulfide bonds in proteins. Only 1% to 2% of Hcy occurs as thiol homocysteine in the serum; 75% of Hcy has been suggested to bind to proteins through disulfide bonds with protein cysteines [6]. Hcy is formed as an intermediary in methionine metabolism [7] [8]. Methionine metabolism mainly occurs in the livers of mammals. Methionine receives an adenosine group from ATP to become S-adenosylmethionine (AdoMet) in the methionine cycle. This reaction is catalyzed in the liver by liver-specific methionine adenosyltransferase I/III (MAT I/III), which is encoded by the methionine adenosyltransferase 1A (MAT1A) gene [9]. AdoMet then transfers its methyl group to a large number of compounds, a process that is catalyzed by various methyltransferases (e.g., glycine N-methyltransferase: GNMT; DNA methyltransferase; phosphatidylethanolamine N-methyl- transferase), to produce S-adenosylhomocysteine (AdoHcy). Hcy is formed from AdoHcy by AdoHcy hydrolase (SAHH). The reaction that generates Hcy from AdoHcy is reversible, and AdoHcy from Hcy is shown to be thermodynamically favored over the synthesis of Hcy [10]. A previous study reported that Hcy levels were very low in the liver [11]. This reaction then proceeds toward the synthesis of Hcy when the products (Hcy and adenosine) are removed by further metabolism [12]. Three enzymes metabolize Hcy, with the betaine-homocysteine S-methyltransferase (BHMT) and methionine synthase (MS) reactions both yielding methionine. A large proportion of Hcy in the liver is remethylated by BHMT [3]. The third enzyme, cystathionine β-synthase (CBS) catalyzes Hcy to cystathionine in the transsulfuration pathway. Previous studies of whole body methionine kinetics demonstrated that 62% of Hcy was converted to cystathionine during each cycle in males fed a basal diet, resulting in the production of glutathione (GSH), while 38% of Hcy was remethylated to methionine [13]. Hcy is located at an important regulatory branch point: remethylation to methionine; conversion to cystathionine; export from the cells.

A decrease in intracellular ATP levels, accompanied by the accumulation of 5’-AMP and subsequently adenosine, is known to follow ischemia. Adenosine levels in interstitial fluids were shown to increase 100 – 1000- fold from basal levels (10 – 300 nM) with ischemia [14]. Furthermore, adenosine levels in hepatocytes were increased by a hypoxic challenge, with excess amounts of adenosine being exported out of cells [14]. Adenosine levels were also found to increase 10-fold due to hypoxia, stress, and inflammation [15]. Adenosine has been shown to activate A1, A2a, and A3 receptors with EC50 values in the range of 0.2 – 0.7 μM, and also A2b receptors with an EC50 of 24 μM [16]. A1 and A3 receptors have been classified as adenylate cyclase inhibitory receptors, and A2a and A2b receptors as adenylate cyclase-activating receptors [17]. The activation of adenosine receptors accompanied by ischemia may increase total Hcy levels in the serum because hepatic ischemia is known to decrease the content of GSH and activity of MAT [18].

We previously reported that the non-specific adenosine receptor agonist 5’-N-ethylcarboxamide-adenosine (NECA) increased serum glucose levels and the expression of a glucogenic enzyme (glucose 6-phosphatase) in the liver [19] [20]. Based on the dose of NECA administered in these studies and plasma concentrations after the administration of other adenosine agonists [21], it was inferred that the serum NECA concentration was in the μM range and also that NECA activated adenosine A2b receptors. In the present study, we measured methionine metabolites, including Hcy, in NECA-treated mice in order to determine whether the activation of adenosine receptors increased total Hcy levels in the serum. The results obtained clearly demonstrated that NECA increased total Hcy levels in the serum.

Measurement of Methionine Metabolites AdoMet and AdoHcy levels in the liver were measured using an HPLC method [25] and total GSH in the liver was measured using a microtiter plate assay [26], as described previously [23]. Total Hcy and total cysteine levels (total Cys: free and protein-bound cysteine) in the serum were measured using an HPLC method [27]. Briefly, a mixture of 50 μL of serum, 25 μL of an internal standard, and 25 μL of phosphate-buffered saline (PBS, pH 7.4) was incubated with 10 μL of 100 mg/mL TCEP for 30 min at room temperature in order to reduce and release protein-bound thiols. After this incubation, 90 μL of 100 mg/mL trichloroacetic acid containing 1 mmol/L EDTA was added for deproteinization, centrifuged at 15,000 ×g for 10 min, and 50 μL of the supernatant was added to a tube containing 10 μL of 1.55 mol/L NaOH; 125 μL of 0.125 mol/L borate buffer containing 4 mmol/L EDTA, pH 9.5; and 50 μL of 1 mg/mL SBD-F in the borate buffer. The sample was then incubated for 60 min at 60˚C. HPLC was performed on a Waters M-600 pump equipped with a Waters 2475 Multi λ Fluorescence Detector (385 nm excitation, 515 nm emission). The separation of SBD-derivatized thiols was performed on a μ-BONDASPHERE C18 column (Waters, 5 μm, 100 A, 150 × 3.9 mm) with a 20-μL injection volume and 0.1 mol/L acetate buffer, pH 5.5, containing 30 ml/L methanol as the mobile phase at a flow rate of 1.0 mL/min and column temperature of 29˚C.

3.1. Effects of NECA on Total Hcy and Total Cys Levels in the Serum As shown in Table 1, serum total Hcy and total Cys levels significantly increased after 16 h of fasting. The administration of a low dose of NECA (NECA0.1 group) to mice fasted for 16 h resulted in higher serum total Hcy levels than those in the control group at 1 h (Experiment 1). Serum total Hcy levels were also significantly elevated at 3 h (Experiment 2), but were not significantly different from those in the control group at 6 h (Experiment 3). The administration of a high dose of NECA (NECA0.3 group) resulted in significantly higher serum total Hcy levels than those in the control group at 1 h, 3 h, 6 h, and 10 h (Experiments 4, 5, 6, and 7), gradually increasing Hcy levels to 19.7 μM. The effects of NECA on serum total Cys levels were the same as those on total Hcy levels.

Table 1. Effects of NECA on the content of total homocysteine and total cysteine in the serum.

3.2. Effects of NECA on Other Methionine Metabolite Levels in the Liver We previously reported that fasting for 16 h decreased AdoMet and GSH levels, and increased AdoHcy levels in the livers of mice [23]. In the present study, as shown in Table 2, the administration of a low dose of NECA (NECA0.1 group) to mice fasted for 16 h resulted in lower liver GSH levels than those in the control group at 1 h (Experiment 1). Liver GSH levels were also significantly lower at 3 h (Experiment 2), while GSH levels were not significantly different from those in the control group at 6 h (Experiment 3). The administration of a high dose of NECA (NECA0.3 group) resulted in liver GSH levels that were significantly lower than those in the control group at 1 h, 6 h, and 10 h (Experiments 4, 6, and 7). The effects of NECA on total Hcy levels in the serum and GSH levels in the liver were similar at each dose and time. Furthermore, the low and high doses of NECA both led to significantly higher AdoMet levels than those in the control group at 1 h (Experiments 1 and 4). AdoMet levels at 3 h, 6 h, and 10 h were not significantly different from those in the control group (Experiments 2, 3, 5, 6, and 7). AdoHcy levels were significantly lower in the NECA0.3 group than in the control group 6 h and 10 h after the administration of NECA (Experiments 6 and 7), while the administration of a low dose of NECA had less of an impact on AdoHcy levels.

Table 2. Effects of NECA on the content of methionine metabolites in the liver.

3.3. Effects of NECA on mRNA Expression of Methionine Cycle Enzymes in the Liver Figure 1 shows changes in the mRNA expression of methionine cycle enzymes in Experiments 4, 5, and 6. The expression of methionine cycle enzymes did not significantly change 1 h after the administration of NECA. The expression of MAT1A mRNA was significantly decreased in the liver 6 h after the NECA treatment, while that of MAT2A was increased. The changes observed in the expression of MAT in the present study were consistent with previous findings obtained in ischemic livers [18] or with liver regeneration [28]. The expression of GNMT, which eliminates excess AdoMet, was significantly decreased 6 h after the NECA treatment. The expression of CBS, which converts Hcy to cystathionine through the transsulfuration pathway, and BHMT, which converts Hcy to methionine, was also decreased at 6 h.

Figure 1 shows changes in the mRNA expression of methionine cycle enzymes in Experiments 4, 5, and 6. The expression of methionine cycle enzymes did not significantly change 1 h after the administration of NECA. The expression of MAT1A mRNA was significantly decreased in the liver 6 h after the NECA treatment, while that of MAT2A was increased. The changes observed in the expression of MAT in the present study were consistent with previous findings obtained in ischemic livers [18] or with liver regeneration [28]. The expression of GNMT, which eliminates excess AdoMet, was significantly decreased 6 h after the NECA treatment. The expression of CBS, which converts Hcy to cystathionine through the transsulfuration pathway, and BHMT, which converts Hcy to methionine, was also decreased at 6 h.

Figure 1. Effects of NECA on the mRNA expression of methionine cycle enzymes in the mouse liver. Northern hybridization was performed on the liver RNA of mice in experiments 4, 5, and 6. The mean ± SEM of the ratio of each enzyme mRNA to the level of the 18S rRNA signal is shown as an arbitrary unit. Unpaired Student’s t-tests were used to compare NECA- treated groups with the control groups. *p < 0.05, **p < 0.01: significantly different from each control.

4. Discussion In the present study, an increase in total Hcy levels and AdoMet levels, and decrease in GSH levels occurred 1 h after the NECA treatment. These results were not due to changes in the expression of methionine metabolic enzymes, which remained unchanged 1 h after the NECA treatment (Figure 1). The effects of NECA on methionine metabolism are summarized in Figure 2. No previous study has demonstrated that adenosine has the ability to directly affect CBS; however, the overproduction of carbon monoxide (CO), which is generated by heme oxygenase (HO), is found to inhibit transsulfuration [11]. CO has been shown to inhibit CBS activity and increase AdoMet concentrations [11]. Adenosine and NECA were previously reported to markedly induce HO in macrophages [29]. Hcy, which is a substrate of CBS, may be increased by NECA via the CO-induced inhibition of CBS, and GSH may be decreased by the CO-induced inhibition of transsulfuration. However, the mechanism by which NECA affects transsulfuration in the short term has not yet been elucidated.

Figure 2. Effects of NECA on the methionine metabolic pathway. MAT: methionine adenosyltransferase, GNMT: glycine N-methyltransferase, CBS: cystathionine β-synthase, BHMT: betaine-homocysteine S-methyltransferase, MS: methionine synthase (Map is based on Sakata SF 2005).

GSH was maintained at a low level for up to 10 h by the NECA0.3 treatment and transsulfuration may have been continuously inhibited by the NECA0.3 treatment. Total Hcy levels were also continuously increased for up to 10 h by the NECA0.3 treatment, and decreased AdoHcy levels were observed 6 h and 10 h after the NECA0.3 treatment. Long-term elevations in serum total Hcy levels by NECA may be maintained by attenuating the expression of methionine metabolic enzymes via the following mechanisms: The expression of methionine metabolic enzymes in the liver was reduced 6 h after the NECA0.3 treatment (Figure 1); the flow of the methionine cycle may have been decreased by changes in the expression of MAT (decreased liver-specific MAT1A expression and increased non-liver type MAT2A expression) because MATIII (Km for methionine: 215 μM – 7 mM) is the true liver-specific isoform responsible for methionine metabolism [30] and the generation rate of AdoMet by MATII (non-liver type enzyme) was modest with a low Km (80 μM for methionine) [31]; inhibition of the methyltransferases, BHMT [32] and GNMT [33], induces hyperhomocysteinemia; decreases in AdoHcy levels may be caused by reductions in methyltransferase levels. However, the mechanisms by which NECA continuously increased total Hcy levels have not yet been elucidated in detail. 5. Conclusion The present study confirmed that the non-specific adenosine receptor agonist NECA continuously increased total Hcy levels in the serum. The inhibition of adenosine receptors may decrease the risk of cardiovascular diseases because an increase in serum total Hcy levels is a known risk factor.

References

[1]	Antoniades, C., Antonopoulos, A.S., Tousoulis, D., Marinou, K. and Stefanadis, C. (2009) Homocysteine and Coronary Atherosclerosis: from Folate Fortification to the Recent Clinical Trials. European Heart Journal, 30, 6-15. http://dx.doi.org/10.1093/eurheartj/ehn515

[2]	Refsum, H., Ueland, P.M., Nygard, O. and Vollset, S.E. (1998) Homocysteine and Cardiovascular Disease. Annual Review of Medicine, 49, 31-62. http://dx.doi.org/10.1146/annurev.med.49.1.31

[3]	Garcia-Tevijano, E.R., Berasain, C., Rodriguez, J.A., Corrales, F.J., Arias, R., Martin-Duce, A., Caballeria, J., Mato, J.M. and Avila, M.A. (2001) Hyperhomocysteinemia in Liver Cirrhosis: Mechanisms and Role in Vascular and Hepatic Fibrosis. Hypertension, 38, 1217-1221. http://dx.doi.org/10.1161/hy1101.099499

[4]	Araki, A., Ito, H., Majima, Y., Hosoi, T. and Orimo, H. (2003) Association between Plasma Homocysteine Concentrations and Asymptomatic Cerebral Infarction or Leukoaraiosis in Elderly Diabetic Patients. Geriatrics & Gerontology International, 3, 15-23. http://dx.doi.org/10.1046/j.1444-1586.2003.00051.x

[5]	Elanchezhian, R., Palsamy, P., Madson, C.J., Lynch, D.W. and Shinohara, T. (2012) Age-Related Cataracts: Homocysteine Coupled Endoplasmic Reticulum Stress and Suppression of Nrf2-Dependent Antioxidant Protection. Chemico-Biological Interactions, 200, 1-10. http://dx.doi.org/10.1016/j.cbi.2012.08.017

[6]	Mudd, S.H., Finkelstein, J.D., Refsum, H., Ueland, P.M., Malinow, M.R., Lentz, S.R., Jacobsen, D.W., Brattstrom, L., Wilcken, B., Wilcken, D.E., Blom, H.J., Stabler, S.P., Allen, R.H., Selhub, J. and Rosenberg, I.H. (2000) Homocysteine and Its Disulfide Derivatives: A Suggested Consensus Terminology. Arteriosclerosis Thrombosis and Vascular Biology, 20, 1704-1706. http://dx.doi.org/10.1161/01.ATV.20.7.1704

[7]	Finkelstein, J.D. (1990) Methionine Metabolism in Mammals. The Journal of Nutritional Biochemistry, 1, 228-237. http://dx.doi.org/10.1016/0955-2863(90)90070-2

[8]	Stipanuk, M.H. (2004) Sulfur Amino Acid Metabolism: Pathways for Production and Removal of Homocysteine and Cysteine. Annual Review of Nutrition, 24, 539-577. http://dx.doi.org/10.1146/annurev.nutr.24.012003.132418

[9]	Chou, J.Y. (2000) Molecular Genetics of Hepatic Methionine Adenosyltransferase Deficiency. Pharmacology & Therapeutics, 85, 1-9. http://dx.doi.org/10.1016/s0163-7258(99)00047-9

[10]	De La Haba, G. and Cantoni, G.L. (1959) The Enzymatic Synthesis of S-Adenosyl-L-Homocysteine from Adenosine and Homocysteine. The Journal of Biological Chemistry, 234, 603-608. http://www.jbc.org/content/234/3/603.short

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reducing obesity-related inflammation

Posted in Clinical Diagnostics, Curation, Diabetes Mellitus, Lipid metabolism, Lipidomics, Liver & Digestive Diseases Research, Metabolism, Nutrition, Nutrition and Phytochemistry, Nutrition Disorders, Obesity, tagged carbohydrate excess, Diabetes, Obesity on November 16, 2015| Leave a Comment »

reducing obesity-related inflammation

Larry H. Bernstein, MD, FCAP, Curator

LPBI

NIH researchers find potential target for reducing obesity-related inflammation

Study sheds light on preventing or reversing certain obesity-associated diseases.

http://www.nih.gov/news-events/news-releases/nih-researchers-find-potential-target-reducing-obesity-related-inflammation

Scientists at the National Institutes of Health have identified a potential molecular target for reducing obesity-related inflammation. Researchers have known that overeating (that is, excess calorie consumption) by individuals with obesity often triggers inflammation, which has been linked to such diseases as asthma and Type 2 diabetes. In their study, published recently in The Journal of Clinical Investigation (Nov. 3, 2015, online version(link is external)), the investigators found that a protein called SIRT3 provides resistance to this inflammatory response and could potentially prevent or reverse obesity-associated diseases of inflammation.

Lead researcher Michael N. Sack, M.D., Ph.D., a senior investigator at NIH’s National Heart, Lung, and Blood Institute, explained that he and his team identified the role of SIRT3 through an investigation involving 19 healthy volunteers who fasted for a 24-hour period.

“Previous research has shown that intermittent fasting or intermittent calorie restriction — by way of eating fewer calories for a few days a month — reduces inflammation,” said Dr. Sack. “We found through our study that this effect is mediated, in part, on a molecular level when SIRT3 blocks the activity of another molecule known as the NLRP3 inflammasome.” He explained that NLRP3 inflammasomes are components of an intracelluar immune response triggered when mitochondria undergo stress, such as from excess calorie intake.

By using cultured cells from a group of eight volunteers who did not fast, Dr. Sack and his team found evidence suggesting that SIRT3 can be activated not only through fasting, but also through the use of nicotinamide riboside, a vitamin B derivative. “Taken together, these early results point to a potential mechanism for addressing obesity-related inflammation, and thus diseases linked to this type of inflammation, such as asthma, Type 2 diabetes, rheumatoid arthritis, and atherosclerosis — conditions associated with a reduced quality of life and/or premature death,” Dr. Sack said.

Obesity remains a substantial health problem for the nation, affecting more than a third of adults and 17 percent of children, according to the Centers for Disease Control and Prevention. Efforts to manage weight, however, can be hindered by the effects of obesity-related diseases. “It is a vicious cycle,” said Dr. Sack. “Take asthma for example. An increase in obesity incidence has been associated with an increase in asthma incidence, but asthma makes it difficult for some to be physically active enough to lose weight.”

Dr. Sack and colleagues — who include researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and Weill Cornell Medical College — are conducting a follow-up study at the NIH Clinical Center to determine whether the vitamin B derivative nicotinamide riboside can specifically reduce bronchial inflammation in individuals with asthma. If the results of the study are promising, Dr. Sack and colleagues will aim to conduct larger clinical trials to validate the findings and potentially inform treatment of obesity-related inflammation in asthma.

The National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at www.nhlbi.nih.gov.

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Seaweed in Diet

Posted in Biochemical pathways, Fatty acids, Liver & Digestive Diseases Research, Metabolism, Metabolomics, Nutrition, Nutrition and Phytochemistry, tagged essential micronutrients, omega3, seaweed on November 15, 2015| Leave a Comment »

Seaweed in Diet

Larry H. Bernstein, MD, FCAP, Curator

LPBI

7 Ways to Eat More Seaweed

http://www.integrativenutrition.com/blog/2015/11/7-ways-to-eat-more-seaweed-and-why-you-should

http://amznstatic01.integrativenutrition.com/styles/panopoly_image_original/shutterstock_255225709.jpg?itok=0EzFp2t6

Seaweed, is making waves again thanks to the discovery of a seaweed that tastes like bacon and is better for you than kale. This could be good news given the World Health Organization’s recent declaration that eating processed meats such as bacon and sausage can increase the risk of colorectal cancer.

But why is seaweed so good for you? And can it actually taste good?

Nutrition-wise, it’s a powerhouse of vitamins and minerals. Seaweeds contain dietary fiber, essential amino acids, vitamins, A, B, C, and E, Omega-3 fats, and minerals such as iodine, calcium, iron, zinc, and magnesium. All of these nutrients combine to reduce inflammation, lift your energy, maintain strong bones and teeth, support thyroid health and hormonal balance, and even reduce your risk of cancer.

It’s no wonder seaweed has been a staple in Asian cuisine for centuries!

While some may have concerns in recent years that seaweed is becoming a potentially harmful food due to the increasing pollution of our oceans, there has not been any evidence to support this despite ongoing testing. That being said, it’s always best to seek out quality products. We recommend finding brands that grow seaweed in sustainable ways and in pure or tested waters.

Let’s get cookin’!

While seaweed hasn’t quite risen to popularity as a superfood like kale or other leafy greens, it’s so versatile and easy to prepare we have a feeling it’ll win you over.

Here are some delicious ways to incorporate more seaweed into your diet:

1. Cook your beans with kombu.
Try adding a strip of kombu when cooking your dried beans to add a rich array of vitamins and minerals to your dish while enhancing the flavor and making the beans more digestible!

2. Snack on nori.
Nori is lightweight and easy to pack yet also nutritious and surprisingly filling. It’s the perfect thing to throw into your bag for a quick snack at work or on the go, and is a healthy alternative for those with salty cravings. Even your kids will enjoy its crispy texture. Want another great way to use nori? Try these delicious seaweed breakfast wraps!

3. Enhance your smoothies with spirulina.
Powdered seaweed such as spirulina is a great source of natural protein, making it a morning and pre- or post-workout favorite among Health Coaches and smoothie-lovers alike. Start with a teaspoon added to your preferred smoothie combo (it goes especially well with avocado, banana, or pineapple) and adjust the amount as you get used to it.

4. Add a dash of seaweed flakes to every meal.
Health food stores or Asian markets will have a variety of packaged salts and seasoning that include seaweed. Or you can make your own by combining fine-chopped or ground nori, kombu, dulse, sea salt, black pepper, and sesame seeds. Keep this right along with your most frequently used seasonings and sprinkle it over daily meals.

5. Mix in kelp or kombu to stocks, soups, and stews.
Add seaweed to any savory liquid-based foods! If you make your own vegetable stock from veggie scraps toss in a strip of seaweed and strain it out along with the other ingredients. If adding directly to soups or stews remove the solid strip before serving but don’t worry about any small pieces left in, they’re edible and will enhance the overall meal.

6. Stir it into your salad dressing.
Sprinkle some powdered seaweed into any salad dressing you’re using, allow it to sit for a minute to mix and absorb, shake well, then toss into your salad.

7. Toss together a seaweed salad.
Wakame and arame are best for a salad made predominantly of seaweed. Combine with vinegar, sesame oil, garlic, and scallions. You can also incorporate other veggies like cucumbers, carrots, or radishes. Experiment to find your favorite combination and share it as a unique side dish at your next potluck.

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Obesity Issues

Posted in Cardiovascular Research, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Clinical & Translational, Curation, Diabetes Mellitus, Disease Biology, Endocrine Diseases, Epigenetics and Cardiovascular Risks, Gene Regulation, Genomic Endocrinology, Lipid metabolism, Lipids, Liver & Digestive Diseases Research, Metabolism, Nutrition, Nutrition Disorders, Nutritional Supplements: Atherogenesis, lipid metabolism, Obesity, tagged ACC1, adipose tissue and adipocyte differentiation, beige fat, brown fat, diet and cell & molecular biology, differentiation, Immunology, Immunometabolism, inflammation, irisin, Memory CD4 T Cells, Metabolism, Obesity, PPARγ, T cell, T2DM, Th17 cell, TNF-α, Weight loss on November 12, 2015| Leave a Comment »

Obesity Issues

Larry H. Bernstein, MD, FCAP, Curator

LPBI

The Changing Face of Obesity

Science tells us obesity is a chronic disease. Why does the outmoded and injurious notion that it is a problem of willpower persist?

By Joseph Proietto | November 1, 2015 http://www.the-scientist.com//?articles.view/articleNo/44288/title/The-Changing-Face-of-Obesity/

In Dante Alighieri’s Divine Comedy the narrator meets a man named Ciacco who had been sent to Hell for the “Damning sin of Gluttony.” According to Catholic theology, in order to end up in Hell one must willfully commit a serious sin. So Dante believed that fat people chose to be fat. This antiquated view of the cause of obesity is still widespread, even among medical professionals. The consequences of this misconception are significant, because it forms the basis for the discrimination suffered by the obese; for the wasting of scarce resources in attempts to change lifestyle habits by public education; and for the limited availability of subsidized obesity treatments.

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While obesity is often labeled a lifestyle disease, poor lifestyle choices alone account for only a 6 to 8 kg weight gain. The body has a powerful negative feedback system to prevent excessive weight gain. The strongest inhibitor of hunger, the hormone leptin, is made by fat cells. A period of increased energy intake will result in fat deposition, which will increase leptin production. Leptin suppresses hunger and increases energy expenditure. This slows down weight gain. To become obese, it may be necessary to harbor a genetic difference that makes the individual resistant to the action of leptin.

Evidence from twin and adoption studies suggests that obesity has a genetic basis, and over the past two decades a number of genes associated with obesity have been described. The most common genetic defect in European populations leading to severe obesity is due to mutations in the gene coding for the melanocortin 4 receptor (MCR4). Still, this defect can explain severe obesity in only approximately 6 percent to 7 percent of cases (J Clin Invest, 106:271-79, 2000). Other genes have been discovered that can cause milder increases in weight; for example, variants of just one gene (FTO) can explain up to 3 kg of weight variation between individuals (Science, 316:889-94, 2007).

Genes do not directly cause weight gain. Rather, genes influence the desire for food and the feeling of satiety. In an environment with either poor access to food or access to only low-calorie food, obesity may not develop even in persons with a genetic predisposition. When there is an abundance of food and a sedentary lifestyle, however, an obesity-prone person will experience greater hunger and reduced satiety, increasing caloric intake and weight gain.

Since the 1980s, there has been a rapid rise in the prevalence of obesity worldwide, a trend that likely results from a variety of complex causes. There is increasing evidence, for example, that the development of obesity on individual or familial levels may be influenced by environmental experiences that occur in early life. For example, if a mother is malnourished during early pregnancy, this results in epigenetic changes to genes involved in the set points for hunger and satiety in the developing child. These changes may then become fixed, resulting in a tendency towards obesity in the offspring.

The biological basis of obesity is further highlighted by the vigorous defense of weight following weight loss. There are at least 10 circulating hormones that modulate hunger. Of these, only one has been confirmed as a hunger-inducing hormone (ghrelin), and it is made and released by the stomach. In contrast, nine hormones suppress hunger, including CCK, PYY, GLP-1, oxyntomodulin, and uroguanylin from the small bowel; leptin from fat cells; and insulin, amylin, and pancreatic polypeptide from the pancreas.

After weight loss, regardless of the diet employed, there are changes in circulating hormones involved in the regulation of body weight. Ghrelin levels tend to increase and levels of multiple appetite-suppressing hormones decrease. There is also a subjective increase in appetite. Researchers have shown that even after three years, these hormonal changes persist (NEJM, 365:1597-604, 2011; Lancet Diabetes and Endocrinology, 2:954-62, 2014). This explains why there is a high rate of weight regain after diet-induced weight loss.

Given that the physiological responses to weight loss predispose people to regain that weight, obesity must be considered a chronic disease. Data show that those who successfully maintain their weight after weight loss do so by remaining vigilant and constantly applying techniques to oppose weight regain. These techniques may involve strict diet and exercise practices and/or pharmacotherapy.

It is imperative for society to move away from a view that obesity is simply a lifestyle issue and to accept that it is a chronic disease. Such a change would not only relieve the stigma of obesity but would also empower politicians, scientists and clinicians to tackle the problem more effectively.

Joseph Proietto was the inaugural Sir Edward Dunlop Medical Research Foundation Professor of Medicine in the Department of Medicine, Austin Health at the University of Melbourne in Australia. He is a researcher and clinician investigating and treating obesity and type 2 diabetes.

A Weighty Anomaly

Why do some obese people actually experience health benefits?

By Jyoti Madhusoodanan | November 1, 2015 http://www.the-scientist.com//?articles.view/articleNo/44304/title/A-Weighty-Anomaly/

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THE ENDOCRINE THEORY: Some researchers have posited that fat cells may secrete molecules that affect glucose homeostasis in muscle or liver tissue.COURTESY OF MITCHELL LAZAR

In the early 19th century, Belgian mathematician Adolphe Quetelet was obsessed with a shape: the bell curve. While helping with a population census, Quetelet proposed that the spread of human traits such as height and weight followed this trend, also known as a Gaussian or normal distribution. On a quest to define a “normal man,” he showed that human height and weight data fell along his beloved bell curves, and in 1823 devised the “Quetelet Index”—more familiar to us today as the BMI, or body mass index, a ratio of weight to height.

Nearly two centuries later, clinicians, researchers, and fitness instructors continue to rely on this metric to pigeonhole people into categories: underweight, healthy, overweight, or obese. But Quetelet never intended the metric to serve as a way to define obesity. And now, a growing body of evidence suggests these categories fail to accurately reflect the health risks—or benefits—of being overweight.

Although there is considerable debate surrounding the prevalence of metabolically healthy obesity, when obesity is defined in terms of BMI (a BMI of 30 or higher), estimates suggest that about 10 percent of adults in the U.S. are obese yet metabolically healthy, while as many as 80 percent of those with a normal BMI may be metabolically unhealthy, with signs of insulin resistance and poor circulating lipid levels, even if they suffer no obvious ill effects. “If all we know about a person is that they have a certain body weight at a certain height, that’s not enough information to know their health risks from obesity,” says health-science researcher Paul McAuley of Winston-Salem State University. “We need better indicators of metabolic health.”

The dangers of being overweight, such as a higher risk of heart disease, type 2 diabetes, and other complications, are well known. But some obese individuals—dubbed the “fat fit”—appear to fare better on many measures of health when they’re heavier. Studies have found lower mortality rates, better response to hemodialysis in chronic kidney disease, and lower incidence of dementia in such people. Mortality, it’s been found, correlates with obesity in a U-shaped curve (J Sports Sci, 29:773-82, 2011). So does extra heft help or hurt?

To answer that question, researchers are trying to elucidate the metabolic reasons for this obesity paradox.

In a recent study, Harvard University epidemiologist Goodarz Danaei and his colleagues analyzed data from nine studies involving a total of more than 58,000 participants to tease apart how obesity and other well-known metabolic risk factors influence the risk of coronary heart disease. Controlling these other risk factors, such as hypertension or high cholesterol, with medication is simpler than curbing obesity itself, Danaei explains. “If you control a person’s obesity you get rid of some health risks, but if you control hypertension or diabetes, that also reduces health risks, and you can do the latter much more easily right now.”

Danaei’s team assessed BMI and metabolic markers such as systolic blood pressure, total serum cholesterol, and fasting blood glucose. The three metabolic markers only explained half of the increased risk of heart disease across all study participants. In obese individuals, the other half appeared to be mediated by fat itself, perhaps via inflammatory markers or other indirect mechanisms (Epidemiology, 26:153-62, 2015). While Danaei’s study was aimed at understanding how obesity hurts health, the results also uncovered unknown mechanisms by which excess adipose tissue might exert its effects. This particular study revealed obesity’s negative effects, but might these unknown mechanisms hold clues that explain the obesity paradox?

Other researchers have suggested additional possibilities—for example, that inflammatory markers such as TNF-α help combat conditions such as chronic kidney disease, or that obesity makes a body more capable of making changes to, and tolerating changes in, blood flow depending on systemic needs (Am J Clin Nutr, 81:543-54, 2005).

According to endocrinologist Mitchell Lazar at the University of Pennsylvania, the key to explaining the obesity paradox may be two nonexclusive ways fat tissue is hypothesized to function. One mechanism, termed the endocrine theory, suggests that fat cells secrete, or don’t secrete enough of, certain molecules that influence glucose homeostasis in other tissues, such as muscle or liver. The first such hormone to be discovered was leptin; later studies reported several other adipocyte-secreted factors, including adiponectin, resistin, and various cytokines.

The other hypothesis, dubbed the spillover theory, suggests that storing lipids in fat cells has some pluses. Adipose tissue might sequester fat-soluble endotoxins, and produce lipoproteins that can bind to and clear harmful lipids from circulation. When fat cells fill up, however, these endotoxins are stashed in the liver, pancreas, or other organs—and that’s when trouble begins. In “fat fit” people, problems typically linked to obesity such as high cholesterol or diabetes may be avoided simply because their adipocytes mop up more endotoxins.

“In this model, one could imagine that if you could store even more fat in fat cells, you could be even more obese, but you might be protected from problems [associated with] obesity because you’re protecting the other tissues from filling up with lipids that cause problems,” says Lazar. “This may be the most popular current model to explain the fat fit.”

Although obesity greatly increases the risk of type 2 diabetes—up to 93-fold in postmenopausal women, for example—not all obese people suffer from the condition. Similarly, a certain subtype of individuals with “normal” BMIs are at greater risk of developing insulin resistance and type 2 diabetes than others with BMIs in the same range. Precisely what distinguishes these two cohorts is still unclear. “Just as important as explaining why some obese people don’t get diabetes is to explain why other subgroups—normal-weight people or those with lipodystrophy—sometimes get it,” Lazar says. “If there are multiple subtypes of obesity and diabetes, can we figure out genetic aspects or biomarkers that cause one of these phenotypes and not the other?”

To Lazar, McAuley, and other researchers, it’s increasingly evident that BMI may not be that metric. Finding better ways to assess a healthy weight, however, has proven challenging. Researchers have tested measures, such as the body shape index (ABSI) or the waist-hip ratio, which attempt to gauge visceral fat—considered to be more metabolically harmful than fat in other body locations. However, these metrics have yet to be implemented widely in clinics, and few are as simple to understand as the BMI (Science, 341:856-58, 2013).

Independent of metrics, however, the health message regarding weight is still unanimous: exercise and healthy dietary choices benefit everyone. “At a certain point, despite all the so-called fit-fat people, the demographics say that there’s a huge risk of diabetes and heart disease at very high BMI,” notes Lazar. “We can’t assume we’ll be one of the lucky ones who will have a BMI in the obese category but will still be protected from heart disease.”

Correction (November 2): The original version of this article misattributed the pull quote above. The attribution for this quote has been corrected, and The Scientist regrets the error.

THE HEALTH RISK OF OBESITY—BETTER METRICS IMPERATIVE

Science 23 Aug 2013; 341(6148): 856–858 DOI: http://dx.doi.org:/10.1126/science.1241244

Obesity paradoxes.

McAuley PA¹, Blair SN. Author information

J Sports Sci. 2011 May;29(8):773-82. http://dx.doi.org:/10.1080/02640414.2011.553965.

In this review, we examine the original obesity paradox phenomenon (i.e. in cardiovascular disease populations, obese patients survive better), as well as three other related paradoxes (pre-obesity, “fat but fit” theory, and “healthy” obesity). An obesity paradox has been reported in a range of cardiovascular and non-cardiovascular conditions. Pre-obesity (defined as a body mass index of 25.0-29.9 kg · m⁻²) presents another paradox. Whereas “overweight” implies increased risk, it is in fact associated with decreased mortality risk compared with normal weight. Another paradox concerns the observation than when fitness is taken into account, the mortality risk associated with obesity is offset. The final paradox under consideration is the presence of a sizeable subset of obese individuals who are otherwise healthy. Consequently, a large segment of the overweight and obese population is not at increased risk for premature death. It appears therefore that low cardiorespiratory fitness and inactivity are a greater health threat than obesity, suggesting that more emphasis should be placed on increasing leisure time physical activity and cardiorespiratory fitness as the main strategy for reducing mortality risk in the broad population of overweight and obese adults.

Obesity, insulin resistance, and cardiovascular disease.

Reaven G¹, Abbasi F, McLaughlin T. Author information

Recent Prog Horm Res. 2004;59:207-23.

The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance – namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations — is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.

Long-Term Persistence of Hormonal Adaptations to Weight Loss

Priya Sumithran, Luke A. Prendergast, Elizabeth Delbridge, Katrina Purcell, Arthur Shulkes, Adamandia Kriketos, and Joseph Proietto

N Engl J Med 2011; 365:1597-1604 October 27, 2011http://dx.doi.org:/10.1056/NEJMoa1105816

After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.

Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).

Full Text of Results…

One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse. (Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number,NCT00870259.)

Full Text of Discussion..

What’s new in endocrinology and diabetes mellitus

Authors Kathryn A Martin, MD Jean E Mulder, MD

FTO variant and obesity (September 2015)

Large genome wide association studies have demonstrated that variants in the FTO gene have the strongest association with obesity risk in the general population, but the mechanism of the association has been unclear. However, a nonocoding causal variant in FTO has now been identified that changes the function of adipocytes from energy utilization (beige fat) to energy storage (white fat) with a fivefold decrease in mitochondrial thermogenesis [17]. When the effect of the variant was blocked in genetically engineered mice, thermogenesis increased and weight gain did not occur, despite eating a high-fat diet. Blocking the gene’s effect in human adipocytes also increased energy utilization. This observation has important implications for potential new anti-obesity drugs. (See “Pathogenesis of obesity”, section on ‘FTO variants’.)

Liraglutide for the treatment of obesity (July 2015)

Along with diet, exercise, and behavior modification, drug therapy may be a helpful component of treatment for select patients who are overweight or obese. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, used for the treatment of type 2 diabetes, and can promote weight loss in patients with diabetes, as well as those without diabetes.

●In a randomized trial in nondiabetic patients who had a body mass index (BMI) of ≥30 kg/m² or ≥27 kg/m² with dyslipidemia and/or hypertension, liraglutide 3 mg once daily, compared with placebo, resulted in greater mean weight loss (-8.0 versus -2.6 kg with placebo) [18]. In addition, cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life improved modestly. Gastrointestinal side effects transiently affected at least 40 percent of the liraglutide group and were the most common reason for withdrawal (6.4 percent). Liraglutide is an option for select overweight or obese patients, although gastrointestinal side effects (nausea, vomiting) and the need for a daily injection may limit the use of this drug. (See “Obesity in adults: Drug therapy”, section on ‘Liraglutide’.)

●In a trial designed specifically to evaluate the effect of liraglutide on weight loss in overweight or obese patients with type 2 diabetes (mean weight 106 kg), liraglutide, compared with placebo, resulted in greater mean weight loss (-6.4 kg and -5.0 kg for liraglutide 3 mg and 1.8 mg, respectively, versus -2.2 kg for placebo) [19]. Treatment with liraglutide was associated with better glycemic control, a reduction in the use of oral hypoglycemic agents, and a reduction in systolic blood pressure. Although liraglutide is not considered as initial therapy for the majority of patients with type 2 diabetes, it is an option for select overweight or obese patients with type 2 diabetes who fail initial therapy with lifestyle intervention and metformin. (See “Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus”, section on ‘Weight loss’.)

The Skinny on Fat Cells

Bruce Spiegelman has spent his career at the forefront of adipocyte differentiation and metabolism.

By Anna Azvolinsky | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44312/title/The-Skinny-on-Fat-Cells/

Bruce Spiegelman
Stanley J. Korsmeyer Professor of Cell Biology
and Medicine
Harvard Medical School
Director, Center for Energy Metabolism
and Chronic
Disease, Dana-Farber Cancer Institute, Boston

It’s hard to know whether you have the right stuff to be a scientist, but I had a passion for the research,” says Bruce Spiegelman, professor of cell biology at Harvard Medical School and the Dana-Farber Cancer Institute. After receiving his PhD in biochemistry from Princeton University in 1978, Spiegelman sent an application to do postdoctoral research to just one lab. “I wasn’t thinking I should apply to five different labs. I just marched forward more or less in a straight line,” he says. Spiegelman did know that he had no financial backup and depended on research fellowships throughout the early phase of his science career. “I thought it was fantastic, and still think so, that a PhD in science is supported by the government. I certainly appreciated that, because many of my friends in the humanities had to support themselves by cobbling together fellowships and teaching every semester, whereas we didn’t face similar challenges in the sciences.”

Since his graduate student days, Spiegelman has realized his potential, pioneering the study of adipose tissue biology and metabolism. He was introduced to the field in Howard Green’s laboratory, then at MIT, where Spiegelman began his one and only postdoc in 1978. Green had recently developed a system for culturing adipose cells and asked Spiegelman if he wanted to study fat cell differentiation. “I knew nothing about adipose tissue, but I was really interested in any model of how one cell switches to another. Whether skin or fat didn’t matter too much to me, because I was not coming at this from the perspective of physiology but from the perspective of how do these switches work at a molecular level?”

Spiegelman has stuck with studying the biology and differentiation of fat cells for more than 30 years. While looking for the master transcriptional regulator of fat development—which his laboratory found in 1994—Spiegelman’s group also discovered one of the first examples of a nuclear oncogene that functions as a transcription factor, and, more recently, the team found that brown fat and white fat come from completely different origins and that brown and beige fat are distinct cell types. Spiegelman was also the first to provide evidence for the connection between inflammation, insulin resistance, and fat tissue.

Here, Spiegelman talks about his strong affinity for the East Coast, his laboratory’s search for molecules that can crank up brown fat production and activity, and the culture of his laboratory’s weekly meeting.

Spiegelman Sets Out

First publication. Spiegelman grew up in Massapequa, New York, a town on Long Island. “Birds, insects, fish, and animals were fascinating to me. As a kid, I imagined I would be a wildlife ranger,” he says. Spiegelman and his brother were the first in their family to attend college; Spiegelman entered the College of William and Mary in 1970 thinking he would major in psychology. But before taking his first psychology course, he had to take a biology course, really loved it, and switched his major. For his senior thesis, he chose one of the few labs that did biochemistry-related research. He studied cultures of the filamentous fungus Aspergillus ornatus in which he induced the upregulation of a metabolic enzyme. Spiegelman applied a calculus transformation that related the age of the culture to the age of individual cells, something that had not been previously done. The work earned him his first first-author publication in 1975. “It was not a great breakthrough, but I think it showed that I was maybe applying myself more than the typical undergraduate.”

Full steam ahead. “My interest in laboratory research was intense. Even though it was not particularly inspired work, the first-author publication in a college where not many of the professors published a lot gave me a lot of confidence. It was probably out of proportion to the quality of the actual work.” That confidence and Spiegelman’s interest in the chemistry of living things led him to pursue a PhD in biochemistry at Princeton University. “Very early on, I felt that I couldn’t understand biology if it didn’t go to the molecular level. To me, just describing how an animal lived without understanding how it worked was very unsatisfying. I think it was one of the best decisions that I made in my life, to do a PhD in biochemistry,” he says, “because if you really want to understand living systems, you are very limited in how you can understand them without having a strong background in biochemistry because these are, essentially, chemical systems.”

Embracing molecular biology. Spiegelman initially joined Arthur Pardee’s laboratory, but switched when Pardee left Princeton for Harvard University in 1975. Because he was already collaborating with Marc Kirschner, a cell biologist and biochemist who studies the regulation of the cell cycle and how the cytoskeleton works, it was an easy transition to transfer to the new laboratory. In Kirschner’s group, Spiegelman became the cell biologist among many protein biochemists working on microtubule assembly in vitro. Rather than understanding how the proteins fit together to form the filamentous structures, Spiegelman wanted to understand what controlled their assembly inside cells. Working in mammalian cells, Spiegelman published three consecutive Cell papers on how microtubule assembly occurs in vivo. The firstpaper, from 1977, demonstrated that a nucleotide functions to stabilize the tubulin molecule rather than to regulate tubulin assembly in vivo.

Spiegelman Simmers

A new tool. For his next move, Spiegelman wanted to marry his background in biochemistry and molecular biology with a good cellular model system. He became interested in differentiation at the end of his PhD, while studying how the cytoskeleton is reorganized during neural differentiation, and settled on Green’s MIT laboratory for his postdoc. Green had developed a way to study both skin and fat cell differentiation. Again, Spiegelman was the odd man out, working on the molecular biology of fat cell differentiation while most of the graduate students and postdocs focused on the cellular biology of skin cell differentiation. While there, Spiegelman learned how to clone cDNA—a new method that some researchers thought was just another new fad, he says. “I thought it was pretty obvious that this was a tool that would be a game changer. I could see how I could clone some of the cDNAs and genes that were regulated in the fat cell lineage and then try to understand the regulation of these genes.”

Setting the stage. Spiegelman demonstrated that cAMP regulates the synthesis of certain enzymes in fat cells during differentiation. But while this was the most influential paper from his postdoc, says Spiegelman, it was his demonstration of cloning mRNAs from adipocytes, published in 1983, that set the stage for cloning fat-selective genes. The work, mostly done when Spiegelman was already a new faculty member at the Dana-Farber Cancer Institute, stemmed from his learning molecular cloning in Phillip Sharp’s lab at MIT and Bryan Roberts’s lab at Harvard. “This was the raw material from which we eventually cloned PPARγ and showed it to be the master regulator of fat [cell] development.”

Roots. Spiegelman became an assistant professor at the Harvard Medical School in 1982, when he was not yet 30. Although he had entertained the idea of moving to the West Coast with his wife, whom he had met at Princeton where she obtained a PhD in French literature, Spiegelman says he is really an East Coaster at heart. “My wife and I came to love Boston and were very comfortable there. Our families were both in New York, which was close, but not too close, and we really enjoyed the culture and pace of Boston; it was more ‘us.’ We really liked to visit California but didn’t particularly want to move there. We’re both real Northeastern people.”

Relating to Sisyphus. The transition from doing a postdoc to setting up his own laboratory was “very exciting and terribly stressful,” says Spiegelman. “When I think back, I always tried to be professional with my laboratory, but I was so stressed at suddenly being on my own with no management training.” The people resources he had encountered in his graduate and postdoctoral training labs were also not there yet, and he says his first publication as a principal investigator was like pushing a rock up a hill. But eventually, Spiegelman’s lab built a reputation and reached a critical mass of talented people who advanced the science. Again in 1983, Spiegelman produced a publication showing that morphological manipulation can affect gene expression and adipose differentiation.

End goal. Spiegelman’s goal was to find a master molecule that orchestrates the conversion of adipocyte precursor cells into bona fide fat cells. Piece by piece, his lab identified the enhancers, promoters, and other regulatory elements involved in adipocyte differentiation. In 1994, graduate student Peter Tontonoz finallyfound that the PPARγ gene, inserted via a retroviral vector into fibroblasts, could induce the cells to become adipose cells. “It took 10 years,” Spiegelman says. Along the way, the laboratory found that c-fos, the product of a famous nuclear oncogene, bound to the promoters of fat-specific genes and worked as a transcription factor. “It was not really known how nuclear oncogenes worked. This was one of the first papers showing that these oncogenes bound to gene promoters and were transcription factors.”

A wider scope. In 1993, graduate student Gökhan Hotamisligil found that tumor necrosis factor-alpha(TNF-α), is induced in the fat tissue of rodent models of obesity and diabetes. The paper sparked the formation of the field of immunometabolism and resulted in the expansion of Spiegelman’s lab into the physiology arena, partly thanks to the guidance of C. Ronald Kahn and Jeff Flier, who both study metabolism and diabetes. But the work initially encountered pushback, says Spiegelman, partly because it was the merging of two fields.

Spiegelman Scales Up

Fat color palette. Brown fat tissue, abundant in infants but scarce in adults, is a metabolically active form of fat that is chock full of mitochondria and is found in pockets in the body distinct from white fat tissue.Pere Puigserver, then a postdoc in Spiegelman’s lab, found that the coactivator PCG-1, binding to PPARγ and other nuclear receptors, could stimulate mitochondrial biogenesis. The PCG-1 gene is turned on by stimuli such as exercise or a cold environment. Later, postdoc Patrick Seale, Spiegelman, and their colleagues showed brown fat cells derive from the same lineage that gives rise to skeletal muscle. “This was a big surprise, maybe the biggest surprise we ever uncovered in the lab,” says Spiegelman.

A paler shade of brown. More recently, in 2012, Spiegelman’s laboratory showed that within adult white adipose tissue, there are pockets of a yet another type of fat tissue that he called beige fat. “I think the evidence is very good from rodents that if you activate brown and beige fat, you get metabolic benefit both in obesity and diabetes. So the question now is: Can that be done in humans in a way that’s beneficial and not toxic?” The lab is now looking to identify molecules that can either ramp up the activity of brown and beige fat or increase the production of both cell types as possible therapeutics for metabolic disorders or even cancer-associated cachexia. “Anyone who says that either approach will work better is being foolish. We just don’t know enough to go after just one or the other.”

On the irisin controversy. After reporting in 2012 that a muscle-related hormone called irisin could switch white fat to metabolically active brown fat, Spiegelman became embroiled in a media-covered debate about whether the molecule really exists; he was also the victim of a potential fraud plot. Most recently, Spiegelman provided thorough evidence that irisin does in fact exist. On the controversy, he says it’s a fine line between defending his scientific integrity and not adding more fuel to the fire or engaging with his harassers. “We have a long track record of doing credible and reproducible science and it was not that complicated to address the paper that claimed irisin was ‘a myth.’ That study used very outmoded scientific approaches.”

Raw talent. Many of Spiegelman’s trainees have gone on to become very successful scientists, including Tontonoz, Hotamisligil, Evan Rosen, and Randy Johnson. “It’s a quantum change in the experience of doing science when you get people who have their own visions. I would have thought that interacting with smart people would mainly help me get my scientific vision accomplished. And that was partly true, but also it changed my vision. When you have people challenging you on a day-to-day basis, you learn from them through the questions they ask and the way they challenge you in a constructive way. They made me a much better scientist.”

Rigorous mentorship. “I feel very passionately that a major part of my job is to prepare the next generation of scientists. Everyone who comes through my lab will tell you that I take that very seriously. We make sure my students give a lot of talks and get critical assessments of their presentations to our lab group. I am very hands-on both scientifically and in developing the way students project their vision. I had a very good mentor, Marc Kirschner, and I’d like to think that I learned how to be a mentor from him. I want to make sure that when people walk out of my lab they are prepared to run independent research programs.”

Greatest Hits

Identified the master regulator of adipogenesis, the nuclear receptor PPARγ
Was the first to show that a nuclear oncogene, c-fos, codes for a transcription factor that binds to the promoters of genes
Demonstrated that adipose tissue synthesizes tumor necrosis factor-alpha (TNF-α), providing the first direct link between obesity, inflammation, insulin resistance, and fat tissue.
Showed that brown fat cells are not developmentally related to white fat
Identified beige fat as a distinct cell type, different from either white or brown fat

Fanning the Flames

Obesity triggers a fatty acid synthesis pathway, which in turn helps drive T cell differentiation and inflammation.

By Kate Yandell | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44306/title/Fanning-the-Flames/

EDITOR’S CHOICE IN IMMUNOLOGY

The paper
Y. Endo et al., “Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1,” Cell Reports, 12:1042-55, 2015.

Cell Rep. 2015 Aug 11;12(6):1042-55. http://dx.doi.org:/10.1016/j.celrep.2015.07.014. Epub 2015 Jul 30.

Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1.

Endo Y¹, Asou HK¹, Matsugae N¹, Hirahara K², Shinoda K¹, Tumes DJ³, Tokuyama H⁴, Yokote K⁴, Nakayama T⁵. Author information

•A high-fat diet augments Th17 cell development and the expression of Acaca
•ACC1 controls Th17 cell development in vitro and Th17 cell pathogenicity in vivo
•ACC1 modulates RORγt function in developing Th17 cells
•Obesity in humans induces ACACA and IL-17A expression in CD4 T cells

Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells.

Figure thumbnail fx1

http://www.cell.com/cms/attachment/2035221719/2050630604/fx1.jpg

http://www.the-scientist.com/November2015/NovMediLit_310px.jpg

FEEDING INFLAMMATION: When mice eat a diet high in fat, their CD4 T cells show increased expression of the fatty acid biosynthesis gene Acaca, which encodes the enzyme ACC1 (1). Products of the ACC1 fatty acid synthesis pathway encourage the transcription factor RORγt to bind near the gene encoding the cytokine IL-17A (2). There, RORγt recruits an enzyme called p300 to modify the genome epigenetically and turn on IL-17A. The memory T cells then differentiate into inflammatory T helper 17 cells.
See full infographic: PDF© STEVE GRAEPEL

Obesity often comes with a side of chronic inflammation, causing inflammatory chemicals and immune cells to flood adipose tissue, the hypothalamus, the liver, and other areas of the body. Inflammation is a big part of what makes obesity such an unhealthy condition, contributing to Type 2 diabetes, heart disease, cancers, autoimmune disorders, and possibly even neurodegenerative diseases.

To better understand the relationship between obesity and inflammation, Toshinori Nakayama, Yusuke Endo, and their colleagues at Chiba University in Japan started with what often leads to obesity: a high-fat diet. They fed mice rich meals for a couple of months and looked at how gene expression in the animals’ T cells compared to gene expression in the T cells of mice fed a normal diet. Most notably, they found increased expression ofAcaca, a gene that codes for a fatty acid synthesis enzyme called acetyl coA carboxylase 1 (ACC1). They went on to show that the resulting increase in fatty acid levels pushed CD4 T cells to differentiate into inflammatory T helper 17 (Th17) cells.

Th17 cells help fight off invading fungi and some bacteria. But these immune cells can also spin out of control in autoimmune diseases such as multiple sclerosis. Nakayama’s team showed that either blocking ACC1 activity with a drug called TOFA or deleting a key portion of Acaca in mouse CD4 T cells reduced the generation of pathologic Th17 cells. Overexpressing Acaca increased Th17-cell generation.

The researchers also demonstrated that mice fed a high-fat diet had elevated susceptibility to a multiple sclerosis–like disease, and that TOFA reduced the symptoms.

“This is a very intriguing finding, suggesting not only that obesity can directly induce Th17 differentiation but also indicating that pharmacologic targeting of fatty acid synthesis may help to interfere with obesity-associated inflammation,” Tim Sparwasser of the Twincore Center for Experimental and Clinical Infection Research in Hannover, Germany, says in an email. Sparwasser and his colleagues had previously shown that ACC1 is required for the differentiation of Th17 cells in mice and humans.

Nakayama explains that CD4 T cells must undergo profound metabolic changes as they mature and differentiate. “The intracellular metabolites, including fatty acids, are essential for cell proliferation and cell growth,” he says in an email. When fatty acid levels in T cells increase, the cells are activated and begin to proliferate.

“It’s a nice illustration of how, really, immune response is so highly connected to the metabolic state of the cell,” says Gökhan S. Hotamisligil of Harvard University’s T.H. Chan School of Public Health who was not involved in the study. “The immune system launches its responses commensurate with the sources of nutrients and energy from the environment,” he adds in an email.

There are still missing pieces in the path from high-fat diet to increased Acaca expression to ACC1’s influence on T-cell differentiation. It also remains to be seen how this plays out in obese humans, although Nakayama and colleagues did show that inhibiting ACC1 reduced pathologic Th17 generation in human immune cell cultures, and that the T cells of obese humans contain elevated levels of ACC1 and show signs of increased differentiation into Th17 cells.

The prevalence of obesity has been increasing worldwide, and obesity is now a major public health problem in most developed countries (Gregor and Hotamisligil, 2011, Ng et al., 2014). Obesity-induced inflammation contributes to the development of various chronic diseases, such as autoimmune diseases, metabolic diseases, and cancer (Kanneganti and Dixit, 2012, Kim et al., 2014,Osborn and Olefsky, 2012, Winer et al., 2009a). A number of studies have pointed out the importance of reciprocal interactions between metabolic systems and immune cells in the pathogenesis of obesity-associated diseases (Kaminski and Randall, 2010, Kanneganti and Dixit, 2012, Kim et al., 2014, Mauer et al., 2014, Stienstra et al., 2012, Winer et al., 2011).

Elucidating the molecular mechanisms by which naive CD4 T cells differentiate into effector T cells is crucial for understanding helper T (Th) cell-mediated immune pathogenicity. After antigen stimulation, naive CD4 T cells differentiate into at least four distinct Th cell subsets: Th1, Th2, Th17, and inducible regulatory T (iTreg) cells (O’Shea and Paul, 2010, Reiner, 2007). Several specific master transcription factors that regulate Th1/Th2/Th17/iTreg cell differentiation have been identified, including T-bet for Th1 (Szabo et al., 2000), GATA3 (Yamashita et al., 2004, Zheng and Flavell, 1997) for Th2, retinoic-acid-receptor-related orphan receptor γt (RORγt) for Th17 (Ivanov et al., 2006), and forkhead box protein 3 (Foxp3) for iTreg (Sakaguchi et al., 2008). The appropriate expression and function of these transcription factors is essential for proper immune regulation by each Th cell subset.

Among these Th cell subsets, Th17 cells contribute to the host defense against fungi and extracellular bacteria (Milner et al., 2008). However, the pathogenicity of IL-17-producing T cells has been recognized in various autoimmune diseases, including multiple sclerosis, psoriasis, inflammatory bowel diseases, and steroid-resistant asthma (Bettelli et al., 2006, Coccia et al., 2012, Ivanov et al., 2006,Leonardi et al., 2012, McGeachy and Cua, 2008, Nylander and Hafler, 2012,Stockinger et al., 2007, Sundrud et al., 2009).

An HFD Promotes Th17 Cell Differentiation and Affects the Expression of Fatty Acid Enzymes in Memory CD4 T Cells In Vivo

Inhibition of ACC1 Function Results in Decreased Th17 Cell Differentiation and Ameliorates the Development of Autoimmune Disease

ACC1 Controls the Differentiation of Th17 Cells Both In Vitro and In Vivo

ACC1 Controls the Function, but Not Expression, of RORγt in Differentiating Th17 Cells

Extrinsic Fatty Acid Supplementation Restored Acaca^−/− Th17 Cell Differentiation through the Functional Improvement of RORγt

Obese Subjects Show Upregulation of ACACA and Increased Th17 Cells in CD45RO⁺ Memory CD4 T Cells

We herein identified a critical role that ACC1 plays in Th17 cell differentiation and the pathogenicity of Th17 cells through the control of the RORγt function under obese circumstances. High-fat-induced obesity augments Th17 cell differentiation and the expression of enzymes involved in fatty acid metabolism, including ACC1. Pharmacological inhibition or genetic deletion of ACC1 resulted in impaired Th17 cell differentiation in both mice and humans. In contrast, overexpression of Acaca induced Th17 cells in vivo, leaving the expression ofIfng and Il4 largely unchanged. ACC1 modulated the binding of RORγt to theIl17a gene and the subsequent p300 recruitment in differentiating Th17 cells. Memory CD4 T cells from peripheral blood mononuclear cells (PBMCs) of obese subjects showed increased IL-17A production and ACACA expression. Furthermore, a strong correlation was detected between the proportion of IL-17A-producing cells and the expression level of ACACA in memory CD4 T cells in obese subjects. Thus, our findings provide evidence of a mechanism wherein obesity can exacerbate IL-17-mediated pathology via the induction of ACC1.

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Irreconciliable Dissonance in Physical Space and Cellular Metabolic Conception

Posted in Amino acids, Anaerobic Glycolysis, Biochemical pathways, Biological Networks, Ca2+ triggered activation, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Chemical Biology and its relations to Metabolic Disease, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Curation, Developmental biology, Disease Biology, DNA repair, Endocrine Diseases, Enzyme Induction, Enzymes and isoenzymes, Epigenetics and Cardiovascular Risks, Fatty acids, Gene Regulation and Evolution, Genome Biology, Genomic Endocrinology, Genomic Expression, Human aging, Human Immune System in Health and in Disease, Inflammasome, Innovations, Ionic Transporters Na+, Lipid metabolism, Liver & Digestive Diseases Research, Metabolism, Metabolomics, Na-K transport, Na-K-ATPase, Neurohumoral Transmission, Neuroscience, Nitric Oxide in Health and Disease, Nutrition, Nutrition and Phytochemistry, Oxidative phosphorylation, Pharmaceutical Analytics, PKC, Population Health Management, Proteins, Proteomics, Pyridine nucleotides, RNA Biology, Synaptic vesicle, Warburg effect, tagged adenine nucleotides, Anaerobic Glycolysis, ATP, Britton Chance, Cancer - General, CO2, electro transport mechanism, Erwin Schroedinger, fermentation, Goedel's Theorem, Goedel-Escher-Bach, H+ transfer, Kurt Goedel, mitochondria, NADH, O2, Oxidative phosphorylation, Pasteur effect, Peter Mitchell, photosynthesis, solar energy, Warburg Effect, yeast on November 11, 2015| Leave a Comment »

Irreconciliable Dissonance in Physical Space and Cellular Metabolic Conception

Curator: Larry H. Bernstein, MD, FCAP

Pasteur Effect – Warburg Effect – What its history can teach us today.

José Eduardo de Salles Roselino

The Warburg effect, in reality the “Pasteur-effect” was the first example of metabolic regulation described. A decrease in the carbon flux originated at the sugar molecule towards the end of the catabolic pathway, with ethanol and carbon dioxide observed when yeast cells were transferred from an anaerobic environmental condition to an aerobic one. In Pasteur´s studies, sugar metabolism was measured mainly by the decrease of sugar concentration in the yeast growth media observed after a measured period of time. The decrease of the sugar concentration in the media occurs at great speed in yeast grown in anaerobiosis (oxygen deficient) and its speed was greatly reduced by the transfer of the yeast culture to an aerobic condition. This finding was very important for the wine industry of France in Pasteur’s time, since most of the undesirable outcomes in the industrial use of yeast were perceived when yeasts cells took a very long time to create, a rather selective anaerobic condition. This selective culture media was characterized by the higher carbon dioxide levels produced by fast growing yeast cells and by a higher alcohol content in the yeast culture media.

However, in biochemical terms, this finding was required to understand Lavoisier’s results indicating that chemical and biological oxidation of sugars produced the same calorimetric (heat generation) results. This observation requires a control mechanism (metabolic regulation) to avoid burning living cells by fast heat released by the sugar biological oxidative processes (metabolism). In addition, Lavoisier´s results were the first indications that both processes happened inside similar thermodynamics limits. In much resumed form, these observations indicate the major reasons that led Warburg to test failure in control mechanisms in cancer cells in comparison with the ones observed in normal cells.

[It might be added that the availability of O₂ and CO₂ and climatic conditions over 750 million years that included volcanic activity, tectonic movements of the earth crust, and glaciation, and more recently the use of carbon fuels and the extensive deforestation of our land masses have had a large role in determining the biological speciation over time, in sea and on land. O2 is generated by plants utilizing energy from the sun and conversion of CO2. Remove the plants and we tip the balance. A large source of CO2 is from beneath the earth’s surface.]

Biology inside classical thermodynamics places some challenges to scientists. For instance, all classical thermodynamics must be measured in reversible thermodynamic conditions. In an isolated system, increase in P (pressure) leads to increase in V (volume), all this occurring in a condition in which infinitesimal changes in one affects in the same way the other, a continuum response. Not even a quantic amount of energy will stand beyond those parameters.

In a reversible system, a decrease in V, under same condition, will led to an increase in P. In biochemistry, reversible usually indicates a reaction that easily goes either from A to B or B to A. For instance, when it was required to search for an anti-ischemic effect of Chlorpromazine in an extra hepatic obstructed liver, it was necessary to use an adequate system of increased biliary system pressure in a reversible manner to exclude a direct effect of this drug over the biological system pressure inducer (bile secretion) in Braz. J. Med. Biol. Res 1989; 22: 889-893. Frequently, these details are jumped over by those who read biology in ATGC letters.

Very important observations can be made in this regard, when neutral mutations are taken into consideration since, after several mutations (not affecting previous activity and function), a last mutant may provide a new transcript RNA for a protein and elicit a new function. For an example, consider a Prion C from lamb getting similar to bovine Prion C while preserving its normal role in the lamb when its ability to change Human Prion C is considered (Stanley Prusiner).

This observation is good enough, to confirm one of the most important contributions of Erwin Schrodinger in his What is Life:

“This little book arose from a course of public lectures, delivered by a theoretical physicist to an audience of about four hundred which did not substantially dwindle, though warned at the outset that the subject matter was a difficult one and that the lectures could not be termed popular, even though the physicist’s most dreaded weapon, mathematical deduction, would hardly be utilized. The reason for this was not that the subject was simple enough to be explained without mathematics, but rather that it was much too involved to be fully accessible to mathematics.”

After Hans Krebs, description of the cyclic nature of the citrate metabolism and after its followers described its requirement for aerobic catabolism two major lines of research started the search for the understanding of the mechanism of energy transfer that explains how ADP is converted into ATP. One followed the organic chemistry line of reasoning and therefore, searched for a mechanism that could explain how the breakdown of carbon-carbon link could have its energy transferred to ATP synthesis. One of the major leaders of this research line was Britton Chance. He took into account that relatively earlier in the series of Krebs cycle reactions, two carbon atoms of acetyl were released as carbon dioxide ( In fact, not the real acetyl carbons but those on the opposite side of citrate molecule). In stoichiometric terms, it was not important whether the released carbons were or were not exactly those originated from glucose carbons. His research aimed at to find out an intermediate proteinaceous intermediary that could act as an energy reservoir. The intermediary could store in a phosphorylated amino acid the energy of carbon-carbon bond breakdown. This activated amino acid could transfer its phosphate group to ADP producing ATP. A key intermediate involved in the transfer was identified by Kaplan and Lipmann at John Hopkins as acetyl coenzyme A, for which Fritz Lipmann received a Nobel Prize.

Alternatively, under possible influence of the excellent results of Hodgkin and Huxley a second line of research appears. The work of Hodgkin & Huxley indicated that the storage of electrical potential energy in transmembrane ionic asymmetries and presented the explanation for the change from resting to action potential in excitable cells. This second line of research, under the leadership of Peter Mitchell postulated a mechanism for the transfer of oxide/reductive power of organic molecules oxidation through electron transfer as the key for the energetic transfer mechanism required for ATP synthesis.
This diverted the attention from high energy (~P) phosphate bond to the transfer of electrons. During most of the time the harsh period of the two confronting points of view, Paul Boyer and followers attempted to act as a conciliatory third party, without getting good results, according to personal accounts (in L. A. or Latin America) heard from those few of our scientists who were able to follow the major scientific events held in USA, and who could present to us later. Paul Boyer could present how the energy was transduced by a molecular machine that changes in conformation in a series of 3 steps while rotating in one direction in order to produce ATP and in opposite direction in order to produce ADP plus Pi from ATP (reversibility).

However, earlier, a victorious Peter Mitchell obtained the result in the conceptual dispute, over the Britton Chance point of view, after he used E. Coli mutants to show H⁺ gradients in the cell membrane and its use as energy source, for which he received a Nobel Prize. Somehow, this outcome represents such a blow to Chance’s previous work that somehow it seems to have cast a shadow over very important findings obtained during his earlier career that should not be affected by one or another form of energy transfer mechanism. For instance, Britton Chance got the simple and rapid polarographic assay method of oxidative phosphorylation and the idea of control of energy metabolism that brings us back to Pasteur.

This metabolic alternative result seems to have been neglected in the recent years of obesity epidemics, which led to a search for a single molecular mechanism required for the understanding of the accumulation of chemical (adipose tissue) reserve in our body. It does not mean that here the role of central nervous system is neglected. In short, in respiring mitochondria the rate of electron transport linked to the rate of ATP production is determined primarily by the relative concentrations of ADP, ATP and phosphate in the external media (cytosol) and not by the concentration of respiratory substrate as pyruvate. Therefore, when the yield of ATP is high as it is in aerobiosis and the cellular use of ATP is not changed, the oxidation of pyruvate and therefore of glycolysis is quickly (without change in gene expression), throttled down to the resting state. The dependence of respiratory rate on ADP concentration is also seen in intact cells. A muscle at rest and using no ATP has a very low respiratory rate. [When skeletal muscle is stressed by high exertion, lactic acid produced is released into the circulation and is metabolized aerobically by the heart at the end of the activity].

This respiratory control of metabolism will lead to preservation of body carbon reserves and in case of high caloric intake in a diet, also shows increase in fat reserves essential for our biological ancestors survival (Today for our obesity epidemics). No matter how important this observation is, it is only one focal point of metabolic control. We cannot reduce the problem of obesity to the existence of metabolic control. There are numerous other factors but on the other hand, we cannot neglect or remove this vital process in order to correct obesity. However, we cannot explain obesity ignoring this metabolic control. This topic is so neglected in modern times that we cannot follow major research lines of the past that were interrupted by the emerging molecular biology techniques and the vain belief that a dogmatic vision of biology could replace all previous knowledge by a new one based upon ATGC readings. For instance, in order to display bad consequences derived from the ignorance of these old scientific facts, we can take into account, for instance, how ion movements across membranes affects membrane protein conformation and therefore contradicts the wrong central dogma of molecular biology. This change in protein conformation (with unchanged amino acid sequence) and/or the lack of change in protein conformation is linked to the factors that affect vital processes as the heart beats. This modern ignorance could also explain some major pitfalls seen in new drugs clinical trials and in a small scale on bad medical practices.

The work of Britton Chance and of Peter Mitchell have deep and sound scientific roots that were made with excellent scientific techniques, supported by excellent scientific reasoning and that were produced in a large series of very important intermediary scientific results. Their sole difference was to aim at very different scientific explanations as their goals (They have different Teleology in their minds made by their previous experiences). When, with the use of mutants obtained in microorganisms P Mitchell´s goal was found to survive and B Chance to succumb to the experimental evidence, all those excellent findings of B Chance and followers were directed to the dustbin of scientific history as an example of lack of scientific consideration. [On the one hand, the Mitchell model used a unicellular organism; on the other, Chance’s work was with eukaryotic cells, quite relevant to the discussion.]

We can resume the challenge faced by these two great scientists in the following form: The first conceptual unification in bioenergetics, achieved in the 1940s, is inextricably bound up with the name of Fritz Lipmann. Its central feature was the recognition that adenosine triphosphate, ATP, serves as a universal energy “currency” much as money serves as economic currency. In a nutshell, the purpose of metabolism is to support the synthesis of ATP. In microorganisms, this is perfect! In humans or mammals, or vertebrates, by the same reason that we cannot consider that gene expression is equivalent to protein function (an acceptable error in the case of microorganisms) this oversimplifies the metabolic requirement with a huge error. However, in case our concern is ATP chemistry only, the metabolism produces ATP and the hydrolysis of ATP pays for the performance of almost, all kinds of works. It is possible to presume that to find out how the flow of metabolism (carbon flow) led to ATP production must be considered a major focal point of research of the two contenders. Consequently, what could be a minor fall of one of the contenders, in case we take into account all that was found during their entire life of research, the real failure in B Chance’s final goal was amplified far beyond what may be considered by reason!

Another aspect that must be taken into account: Both contenders have in the scientific past a very sound root. Metabolism may produce two forms of energy currency (I personally don´t like this expression*) and I use it here because it was used by both groups in order to express their findings. Together with simplistic thermodynamics, this expression conveys wrong ideas): The second kind of energy currency is the current of ions passing from one side of a membrane to the other. The P. Mitchell scientific root undoubtedly have the work of Hodgkin & Huxley, Huxley & Huxley, Huxley & Simmons

*ATP is produced under the guidance of cell needs and not by its yield. When glucose yields only 2 ATPs per molecule it is oxidized at very high speed (anaerobiosis) as is required to match cellular needs. On the other hand, when it may yield (thermodynamic terms) 38 ATP the same molecule is oxidized at low speed. It would be similar to an investor choice its least money yield form for its investment (1940s to 1972) as a solid support. B. Chance had the enzymologists involved in clarifying how ATP could be produced directly from NADH + H⁺ oxidative reductive metabolic reactions or from the hydrolysis of an enolpyruvate intermediary. Both competitors had their work supported by different but, sound scientific roots and have produced very important scientific results while trying to present their hypothetical point of view.

Before the winning results of P. Mitchell were displayed, one line of defense used by B. Chance followers was to create a conflict between what would be expected by a restrictive role of proteins through its specificity ionic interactions and the general ability of ionic asymmetries that could be associated with mitochondrial ATP production. Chemical catalyzed protein activities do not have perfect specificity but an outstanding degree of selective interaction was presented by the lock and key model of enzyme interaction. A large group of outstanding “mitochondriologists” were able to show ATP synthesis associated with Na⁺, K⁺, Ca²⁺… asymmetries on mitochondrial membranes and any time they did this, P. Mitchell have to display the existence of antiporters that exchange X for hydrogen as the final common source of chemiosmotic energy used by mitochondria for ATP synthesis.

This conceptual battle has generated an enormous knowledge that was laid to rest, somehow discontinued in the form of scientific research, when the final E. Coli mutant studies presented the convincing final evidence in favor of P. Mitchell point of view.

Not surprisingly, a “wise anonymous” later, pointed out: “No matter what you are doing, you will always be better off in case you have a mutant”

(Principles of Medical Genetics T D Gelehrter & F.S. Collins chapter 7, 1990).

However, let’s take the example of a mechanical wristwatch. It clearly indicates when the watch is working in an acceptable way, that its normal functioning condition is not the result of one of its isolated components – or something that can be shown by a reductionist molecular view. Usually it will be considered that it is working in an acceptable way, in case it is found that its accuracy falls inside a normal functional range, for instance, one or two standard deviations bellow or above the mean value for normal function, what depends upon the rigor wisely adopted. While, only when it has a faulty component (a genetic inborn error) we can indicate a single isolated piece as the cause of its failure (a reductionist molecular view).

We need to teach in medicine, first the major reasons why the watch works fine (not saying it is “automatic”). The functions may cross the reversible to irreversible regulatory limit change, faster than what we can imagine. Latter, when these ideas about normal are held very clear in the mind set of medical doctors (not medical technicians) we may address the inborn errors and what we may have learn from it. A modern medical technician may cause admiration when he uses an “innocent” virus to correct for a faulty gene (a rather impressive technological advance). However, in case the virus, later shows signals that indicate that it was not so innocent, a real medical doctor will be called upon to put things in correct place again.

Among the missing parts of normal evolution in biochemistry a lot about ion fluxes can be found. Even those oscillatory changes in Ca²⁺ that were shown to affect gene expression (C. De Duve) were laid to rest since, they clearly indicate a source of biological information that despite the fact that it does not change nucleotides order in the DNA, it shows an opposing flux of biological information against the dogma (DNA to RNA to proteins). Another, line has shown a hierarchy, on the use of mitochondrial membrane potential: First the potential is used for Ca²⁺ uptake and only afterwards, the potential is used for ADP conversion into ATP (A. L. Lehninger). In fact, the real idea of A. L. Lehninger was by far, more complex since according to him, mitochondria works like a buffer for intracellular calcium releasing it to outside in case of a deep decrease in cytosol levels or capturing it from cytosol when facing transient increase in Ca²⁺ load. As some of Krebs cycle dehydrogenases were activated by Ca^2+, this finding was used to propose a new control factor in addition to the one of ADP (B. Chance). All this was discontinued with the wrong use of calculus (today we could indicate bioinformatics in a similar role) in biochemistry that has established less importance to a mitochondrial role after comparative kinetics that today are seen as faulty.

It is important to combat dogmatic reasoning and restore sound scientific foundations in basic medical courses that must urgently reverse the faulty trend that tries to impose a view that goes from the detail towards generalization instead of the correct form that goes from the general finding well understood towards its molecular details. The view that led to curious subjects as bioinformatics in medical courses as training in sequence finding activities can only be explained by its commercial value. The usual form of scientific thinking respects the limits of our ability to grasp new knowledge and relies on reproducibility of scientific results as a form to surpass lack of mathematical equation that defines relationship of variables and the determination of its functional domains. It also uses old scientific roots, as its sound support never replaces existing knowledge by dogmatic and/or wishful thinking. When the sequence of DNA was found as a technical advance to find amino acid sequence in proteins it was just a technical advance. This technical advance by no means could be considered a scientific result presented as an indication that DNA sequences alone have replaced the need to study protein chemistry, its responses to microenvironmental changes in order to understand its multiple conformations, changes in activities and function. As E. Schrodinger correctly describes the chemical structure responsible for the coded form stored of genetic information must have minimal interaction with its microenvironment in order to endure hundreds and hundreds years as seen in Hapsburg’s lips. Only magical reasoning assumes that it is possible to find out in non-reactive chemical structures the properties of the reactive ones.

For instance, knowledge of the reactions of the Krebs cycle clearly indicate a role for solvent that no longer could be considered to be an inert bath for catalytic activity of the enzymes when the transfer of energy include a role for hydrogen transport. The great increase in understanding this change on chemical reaction arrived from conformational energy.

Again, even a rather simplistic view of this atomic property (Conformational energy) is enough to confirm once more, one of the most important contribution of E. Schrodinger in his What is Life:

In a very simplistic view, while energy manifests itself by the ability to perform work conformational energy as a property derived from our atomic structure can be neutral, positive or negative (no effect, increased or decreased reactivity upon any chemistry reactivity measured as work)

Also:

“I mean the fact that we, whose total being is entirely based on a marvelous interplay of this very kind, yet if all possess the power of acquiring considerable knowledge about it. I think it possible that this knowledge may advance to little just a short of a complete understanding -of the first marvel. The second may well be beyond human understanding.”

In fact, scientific knowledge allows us to understand how biological evolution may have occurred or have not occurred and yet does not present a proof about how it would have being occurred. It will be always be an indication of possible against highly unlike and never a scientific proven fact about the real form of its occurrence.

As was the case of B. Chance in its bioenergetics findings, we may get very important findings that indicates wrong directions in the future as was his case, or directed toward our past.

The Skeleton of Physical Time – Quantum Energies in Relative Space of S-labs

By Radoslav S. Bozov Independent Researcher

WSEAS, Biology and BioSystems of Biomedicine

Space does not equate to distance, displacement of an object by classically defined forces – electromagnetic, gravity or inertia. In perceiving quantum open systems, a quanta, a package of energy, displaces properties of wave interference and statistical outcomes of sums of paths of particles detected by a design of S-labs.

The notion of S-labs, space labs, deals with inherent problems of operational module, R(i+1), where an imagination number ‘struggles’ to work under roots of a negative sign, a reflection of an observable set of sums reaching out of the limits of the human being organ, an eye or other foundational signal processing system.

While heavenly bodies, planets, star systems, and other exotic forms of light reflecting and/or emitting objects, observable via naked eye have been deduced to operate under numerical systems that calculate a periodic displacement of one relative to another, atomic clocks of nanospace open our eyes to ever expanding energy spaces, where matrices of interactive variables point to the problem of infinity of variations in scalar spaces, however, defining properties of minute universes as a mirror image of an astronomical system. The first and furthermost problem is essentially the same as those mathematical methodologies deduced by Isaac Newton and Albert Einstein for processing a surface. I will introduce you to a surface interference method by describing undetermined objective space in terms of determined subjective time.

Therefore, the moment will be an outcome of statistical sums of a numerical system extending from near zero to near one. Three strings hold down a dual system entangled via interference of two waves, where a single wave is a product of three particles (today named accordingly to either weak or strong interactions) momentum.

The above described system emerges from duality into trinity the objective space value of physical realities. The triangle of physical observables – charge, gravity and electromagnetism, is an outcome of interference of particles, strings and waves, where particles are not particles, or are strings strings, or are waves waves of an infinite character in an open system which we attempt to define to predict outcomes of tomorrow’s parameters, either dependent or independent as well as both subjective to time simulations.

We now know that aging of a biological organism cannot be defined within singularity. Thereafter, clocks are subjective to apparatuses measuring oscillation of defined parameters which enable us to calculate both amplitude and a period, which we know to be dependent on phase transitions.

The problem of phase was solved by the applicability of carbon relative systems. A piece of diamond does not get wet, yet it holds water’s light entangled property. Water is the dark force of light. To formulate such statement, we have been searching truth by examining cooling objects where the Maxwell demon is translated into information, a data complex system.

Modern perspectives in computing quantum based matrices, 0+1 =1 and/or 0+0=1, and/or 1+1 =0, will be reduced by applying a conceptual frame of Aladdin’s flying anti-gravity carpet, unwrapping both past and future by sending a photon to both, placing present always near zero. Thus, each parallel quantum computation of a natural system approaching the limit of a vibration of a string defining 0 does not equal 0, and 1 does not equal 1. In any case, if our method 1+1 = 1, yet, 1 is not 1 at time i+1. This will set the fundamentals of an operational module, called labris operator or in simplicity S-labs. Note, that 1 as a result is an event predictable to future, while interacting parameters of addition 1+1 may be both, 1 as an observable past, and 1 as an imaginary system, or 1+1 displaced interactive parameters of past observable events. This is the foundation of Future Quantum Relative Systems Interference (QRSI), taking analytical technologies of future as a result of data matrices compressing principle relative to carbon as a reference matter rational to water based properties.

Goedel’s concept of loops exist therefore only upon discrete relative space uniting to parallel absolute continuity of time ‘lags’. ( Goedel, Escher and Bach: An Eternal Golden Braid. A Metaphorical Fugue on Minds and Machines in the Spirit of Lewis Carroll. D Hofstadter. Chapter XX: Strange Loops, Or Tangled Hierarchies. A grand windup of many of the ideas about hierarchical systems and self-reference. It is concerned with the snarls which arise when systems turn back on themselves-for example, science probing science, government investigating governmental wrongdoing, art violating the rules of art, and finally, humans thinking about their own brains and minds. Does Gödel’s Theorem have anything to say about this last “snarl”? Are free will and the sensation of consciousness connected to Gödel’s Theorem? The Chapter ends by tying Gödel, Escher, and Bach together once again.) The fight struggle in-between time creates dark spaces within which strings manage to obey light properties – entangled bozons of information carrying future outcomes of a systems processing consciousness. Therefore, Albert Einstein was correct in his quantum time realities by rejecting a resolving cube of sugar within a cup of tea (Henri Bergson 19th century philosopher. Bergson’s concept of multiplicity attempts to unify in a consistent way two contradictory features: heterogeneity and continuity. Many philosophers today think that this concept of multiplicity, despite its difficulty, is revolutionary.) However, the unity of time and space could not be achieved by deducing time to charge, gravity and electromagnetic properties of energy and mass.

Charge is further deduced to interference of particles/strings/waves, contrary to the Hawking idea of irreducibility of chemical energy carrying ‘units’, and gravity is accounted for by intrinsic properties of anti-gravity carbon systems processing light, an electromagnetic force, that I have deduced towards ever expanding discrete energy space-energies rational to compressing mass/time. The role of loops seems to operate to control formalities where boundaries of space fluctuate as a result of what we called above – dark time-spaces.

Indeed, the concept of horizon is a constant due to ever expanding observables. Thus, it fails to acquire a rational approach towards space-time issues.

Richard Feynman has touched on issues of touching of space, sums of paths of particle traveling through time. In a way he has resolved an important paradigm, storing information and possibly studying it by opening a black box. Schroedinger’s cat is alive again, but incapable of climbing a tree when chased by a dog. Every time a cat climbs a garden tree, a fruit falls on hedgehogs carried away parallel to living wormholes whose purpose of generating information lies upon carbon units resolving light.

In order to deal with such a paradigm, we will introduce i+1 under square root in relativity, therefore taking negative one ( -1 = sqrt (i+1), an operational module R dealing with Wheelers foam squeezed by light, releasing water – dark spaces. Thousand words down!

What is a number? Is that a name or some kind of language or both? Is the issue of number theory possibly accountable to the value of the concept of entropic timing? Light penetrating a pyramid holding bean seeds on a piece of paper and a piece of slice of bread, a triple set, where a church mouse has taken a drop of tear, but a blood drop. What an amazing physics! The magic of biology lies above egoism, above pride, and below Saints.

We will set up the twelve parameters seen through 3+1 in classic realities:

– discrete absolute energies/forces – no contradiction for now between Newtonian and Albert Einstein mechanics

– mass absolute continuity – conservational law of physics in accordance to weak and strong forces

– quantum relative spaces – issuing a paradox of Albert Einstein’s space-time resolved by the uncertainty principle

– parallel continuity of multiple time/universes – resolving uncertainty of united space and energy through evolving statistical concepts of scalar relative space expansion and vector quantum energies by compressing relative continuity of matter in it, ever compressing flat surfaces – finding the inverse link between deterministic mechanics of displacement and imaginary space, where spheres fit within surface of triangles as time unwraps past by pulling strings from future.

To us, common human beings, with an extra curiosity overloaded by real dreams, value happens to play in the intricate foundation of life – the garden of love, its carbon management in mind, collecting pieces of squeezed cooling time.

The infinite interference of each operational module to another composing ever emerging time constrains unified by the Solar system, objective to humanity, perhaps answers that a drop of blood and a drop of tear is united by a droplet of a substance separating negative entropy to time courses of a physical realities as defined by an open algorithm where chasing power subdue to space becomes an issue of time.

Jose Eduardo de Salles Roselino

Some small errors: For intance an increase i P leads to a decrease in V ( not an increase in V)..

Radoslav S. Bozov Independent Researcher

If we were to use a preventative measures of medical science, instruments of medical science must predict future outcomes based on observable parameters of history….. There are several key issues arising: 1. Despite pinning a difference on genomic scale , say pieces of information, we do not know how to have changed that – that is shift methylome occupying genome surfaces , in a precise manner.. 2. Living systems operational quo DO NOT work as by vector gravity physics of ‘building blocks. That is projecting a delusional concept of a masonry trick, who has not worked by corner stones and ever shifting momenta … Assuming genomic assembling worked, that is dealing with inferences through data mining and annotation, we are not in a position to read future in real time, and we will never be, because of the rtPCR technology self restriction into data -time processing .. We know of existing post translational modalities… 3. We don’t know what we don’t know, and that foundational to future medicine – that is dealing with biological clocks, behavior, and various daily life inputs ranging from radiation to water systems, food quality, drugs…

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Phase I/II Hepato-specific Glucokinase Activator

Posted in Cell Biology, Chemical Biology and its relations to Metabolic Disease, Clinical & Translational, Curation, Diabetes Mellitus, Diagnostics and Lab Tests, Disease Biology, Endocrine Diseases, Enzymes and isoenzymes, Epigenetics and Cardiovascular Risks, FDA, Gastroenterology, Gene Regulation, Genomic Testing: Methodology for Diagnosis, Innovations, Intellectual Property, International Global Work in Pharmaceutical, Kinase, Metabolism, Metabolomics, Nutrition, Origins of Cardiovascular Disease, Patents, Personal Health Applications: Tech Innovations serves HealhCare, Pharmaceutical Analytics, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, tagged glucokinase activator, glucokinase inhibitor, liver specificity, pharmaceutical innovation, T2DM on November 10, 2015| Leave a Comment »

Phase I/II Hepato-specific Glucokinase Activator

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Advinus Therapeutics announced that it has successfully completed a 14-day POC study in 60 Type II diabetic patients on its lead molecule, GKM-001, a glucokinase activator. The results of the trial show effective glucose lowering across all doses tested without any incidence of hypoglycemia or any other clinically relevant adverse events.

GKM-001 is differentiated from most other GK molecules that are in development, or have been discontinued, due to its novel liver selective mechanism of action.

GKM 001 in pipeline for Diabetes by Advinus

by DR ANTHONY MELVIN CRASTO Ph.D

https://newdrugapprovals.files.wordpress.com/2015/11/ad-1.jpg

GKM 001

Advinus Therapeutics Private L,

A glucokinase activator for treatment of type II diabetes, currently in PI. Advinus is actively exploring partnership options to expedite further development and WW marketing of GKM-001.

Company	Advinus Therapeutics Ltd.
Description	Activator of glucokinase (GCK; GK)
Molecular Target	Glucokinase (GCK) (GK)
Mechanism of Action	Glucokinase activator
Therapeutic Modality	Small molecule

Latest Stage of Development	Phase I/II
Standard Indication	Diabetes
Indication Details	Treat Type II diabetes

PATENT

https://www.google.co.in/patents/WO2009047798A2?cl=en

Example Cl : (-)-{5-ChIoro-2-[2-(4-cyclopropanesulfonylphenyI)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}-acetic acid, ethyl ester
¹H NMR(400 MHz, CDCl₃): δ 1.06-1.08 (m, 2H), 1.30 (t, J=7.2 Hz, 3H), 1.33-1.38 (m, 2H), 2.42-2.50 (m, IH), 3.73 (d, J=2 Hz, 2H), 4.22 (q, J=7.2 Hz ,2H), 5.75 (s, IH), 6.76- 6.77 (m, IH), 6.83-6.86 (m, IH), 6.90-6.98 (m, IH), 7.73 (d, J=8.4 Hz, 2H), 7.96 (d, J=8.4 Hz, 2H), 9.96 (bs, IH). MS (EI) m/z: 571.1 and 573.1 (M+ 1; for ³⁵Cl and ³⁷Cl respectively).

Examples C2 and C3 were prepared in analogues manner of example (Cl) from the appropriate chiral intermediate:

Example Dl : (+)-{5-Chloro-2-[2-(4-cyclopropanesulfonylphenyl)-2-(2,4- difluorophenoxy)acetylamino]thiazol-4-yl}acetic acid, ethyl ester

Advinus’ GK-activator Achieves Early POC for Diabetes

November 29 2011

Partnership Dialog Actively Underway

Advinus Therapeutics, a research-based pharmaceutical company founded by globally experienced industry executives and promoted by the TATA Group, announced that it has successfully completed a 14-day POC study in 60 Type II diabetic patients on its lead molecule, GKM-001, a glucokinase activator. The results of the trial show effective glucose lowering across all doses tested without any incidence of hypoglycemia or any other clinically relevant adverse events.

The clinical trials on GKM-001 validate the company’s pre-clinical hypothesis that a liver selective Glucokinase activator would not cause hypoglycemia (very low blood sugar), while showing robust efficacy.

“GKM-001 is differentiated from most other GK molecules that are in development, or have been discontinued, due to its novel liver selective mechanism of action. GKM-001 has a prolonged pharmacological effect and a half-life that should support a once a day dosing as both mono and combination therapy.” said Dr. Rashmi Barbhaiya, MD & CEO, Advinus Therapeutics. He added that Advinus is actively exploring partnership options to expedite further development and global marketing of GKM-001.

GKM-001 belongs to a novel class of molecules for treatment of type II diabetes. It is an activator of Glucokinase (GK), a glucose-sensing enzyme found mainly in the liver and pancreas. Being liver selective, GKM-001 mostly activates GK in the liver and not in pancreas, which is its key differentiation from most competitor molecules that activate GK in pancreas as well. The resulting increase in insulin secretion creates a potential for hypoglycemia-a risk GKM-001 is designed to avoid. Advinus has the composition of matter patent on GKM-001 for all major markets globally. Both the Single Ascending Dose data, in healthy and type II diabetics, and the Multiple Ascending Dose Study in Type II diabetics has shown that the molecule shows effective glucose lowering in a dose dependent manner and has excellent safety and tolerability profile over a 40-fold dose range. The pharmacokinetic properties of the molecule support once a day dosing. GKM-001 has the potential to be “First-in-Class” drug to address this large, growing and yet poorly addressed market.

Advinus also has identified a clinical candidate as a back-up to GKM-001, which is structurally different. In its portfolio, the company has a growing pipeline for COPD, sickle cell disease, inflammatory bowel disease, type 2 diabetes, acute and chronic pain and rheumatoid arthritis in various stages of late discovery and pre-clinical development.

Advinus Therapeutics team discovers novel molecule for treatment of diabetes

The first glucokinase modulator discovered and developed in India
A new concept for the management of diabetes for patients, globally
100 per cent ‘made in India’ molecule for the treatment of diabetes
IND approved by DGCI, Phase I clinical trial shows excellent safety and tolerance profiles with efficacy

Bangalore: Advinus Therapeutics (Advinus), the research-based pharmaceutical company founded by leading global pharmaceutical executives and promoted by the Tata group, today, announced the discovery of a novel molecule for the treatment of type II diabetes — GKM-001.The molecule is an activator of glucokinase; an enzyme that regulates glucose balance and insulin secretion in the body.

GKM-001 is a completely indigenously developed molecule and the initial clinical trials have shown excellent results for both safety and efficacy.

“Considering past failures of other companies on this target, our discovery programme primarily focused on identifying a molecule that would be efficacious without causing hypoglycaemia; a side effect associated with most compounds developed for this target.

“Recently completed Phase I data indicate that Advinus’ GKM–001 is a liver selective molecule that has overcome the biggest clinical challenge of hypoglycaemia. GKM-001 is differentiated from most other GK molecules in development due to this novel mechanism of action,” said Dr Rashmi Barbhaiya, MD and CEO, Advinus Therapeutics.

He further added, “We are very proud that GKM-001 is 100 per cent Indian. Advinus’s discovery team in Pune discovered the molecule and entire preclinical development was carried out at our centre in Bangalore. The Investigational New Drug (IND) application was filed with the DGCI for approval to initiate clinical trials in India within 34 months of initiation of the discovery programme. Subsequent to the approval of the IND, we have completed the Phase I Single Ascending Dose study in India within two months.”

GKM-001 is a novel molecule for the treatment of type II diabetes. It is the first glucokinase modulator discovered and developed in India and has potential to be both first or best in class. The success in discovering GKM-001 is attributed to the science-driven efforts in Advinus laboratories and ‘breaking the conventional mold’ for selection of a drug candidate. Advinus has ‘composition of matter’ patent on the molecule for all major markets globally. Glucokinase as a class of target is considered to be novel as currently there is no product in the market or in late clinical trials. The strategy for early clinical development revolved around assessing safety (particularly hypoglycaemia) and early assessment of therapeutic activity (glucose lowering and other biomarkers) in type II diabetics. The Phase I data, in both healthy and type II diabetics, shows excellent safety and tolerability over a 40-fold dose range and desirable pharmacokinetic properties consistent with ‘once a day’ dosing. The next wave of clinical studies planned continues on this strategy of early testing in type II diabetics.

Right behind the lead candidate GKM-001, Advinus has a rich pipeline of back up compounds on the same target. These include several structurally different compounds with diverse potency, unique pharmacology and tissue selectivity. Having discovered the molecule with early indication of wide safety margins, desired efficacy and pharmacokinetic profiles, the company now seeks to out-licence GKM-001 and its discovery portfolio.

Liver Selective Glucokinase Activation for Treating Type 2 Diabetes: Translation fromMouse to Man

Kasim A. Mookhtiar, , Debnath Bhuniya, Siddhartha De, Anita Chugh, Jayasagar

Gundu, Venkata Palle, Dhananjay Umrani, Nimish Vachharajani, Vikram

Ramanathan and Rashmi H. Barbhaiya

Advinus Therapeutics Ltd, Hinjewadi, Pune – 411057, and Peenya Industrial Area,

Bangalore – 560058, India

REFERENCES

http://www.asiabiotech.com/publication/apbn/14/english/preserved-docs/1410/0043_0043.pdf

http://www.thepharmatimes.in/index.php/news/general/national/268-advinus-gk-activator-achieves-early-poc-for-diabetes

http://ctri.nic.in/clinicaltrials/pmaindet2.php?trialid=2869

patent

wo 2008104994

wo 2008 149382

wo 2009047798

WO2008104994A2*

25 Feb 2008

4 Sep 2008

Advinus Therapeutics Private L

2,2,2-tri-substituted acetamide derivatives as glucokinase activators, their process and pharmaceutical application

///////GKM 001, pipeline, Diabetes, Advinus, type II diabetes, glucokinase modulator, Rashmi Barbhaiya

DR ANTHONY MELVIN CRASTO Ph.D | November 10, 2015 at 12:55 pm | Tags: Advinus,DIABETES, GKM 001, glucokinase modulator, pipeline, Rashmi Barbhaiya, type II diabetes | Categories: Uncategorized | URL: http://wp.me/p38LX5-44G

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Blood Pressure Lowering

Posted in Atherogenic Processes & Pathology, Cardiovascular Research, Clinical & Translational, Curation, Diagnostics and Lab Tests, Epigenetics and Cardiovascular Risks, History and physical exam, HTN, Nutrition, Origins of Cardiovascular Disease, Population Health Management, Population Health Management, Nutrition and Phytochemistry, tagged blood pressure lowering, Clinical Trials, CVD risk, Hypertension on November 10, 2015| Leave a Comment »

Blood Pressure Lowering

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Data analysis and publication of landmark NIH blood pressure study confirm that lower blood pressure target can reduce cardiovascular disease, deaths

http://www.nih.gov/news-events/news-releases/data-analysis-publication-landmark-nih-blood-pressure-study-confirm-lower-blood-pressure-target-can-reduce-cardiovascular-disease-deaths

NIH-supported researchers are reporting more details on a landmark study that announced preliminary findings in September showing a lower blood pressure target can save lives and reduce the risk of cardiovascular disease in a group of non-diabetic adults 50 years and older with high blood pressure. Results of the Systolic Blood Pressure Intervention Trial (SPRINT) appear in the current online issue of the New England Journal of Medicine and were discussed today at the American Heart Association 2015 Scientific Sessions in Orlando.

The study confirms that, in adults 50 years and older with high blood pressure, targeting a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) reduced rates of cardiovascular events, such as heart attack and heart failure, as well as stroke, by 25 percent. Additionally, this target reduced the risk of death by 27 percent—as compared to a target systolic pressure of 140 mm Hg.

“SPRINT is part of a proud legacy of NIH-funded clinical trials that will change clinical practice and save lives for decades to come. These results reinforce the compelling public health importance of enhancing the awareness, treatment and control of hypertension in this country and around the world,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor of SPRINT.

The SPRINT study, which began in the fall of 2009, included more than 9,300 participants age 50 and older, recruited from about 100 medical centers and clinical practices throughout the United States and Puerto Rico. About 36 percent of participants were women, 58 percent were white, 30 percent were African-American, and 11 percent were Hispanic. The SPRINT study did not include patients with diabetes, prior stroke, or polycystic kidney disease, as other NIH trials were studying those particular populations. Approximately 28 percent were 75 or older and 28 percent had chronic kidney disease. The study tested a strategy of using blood pressure medications to achieve the targeted goals of less than 120 mm Hg (intensive treatment group) versus 140 mm Hg (standard treatment group). The NIH stopped the blood pressure intervention in August—a year earlier than planned—after it became apparent that this more intensive intervention was beneficial.

“When the benefits of the stronger intervention became apparent in SPRINT, we made a commitment to rapid public health communication and peer-reviewed publication of the study results,” Dr. Gibbons said. “We are pleased to present the details of the study’s potentially lifesaving findings at this time.”

In their report, investigators provided detailed data showing that both cardiovascular deaths and overall deaths were lower in the intensive treatment group.

Certain types of serious consequences were more common in the intensive group, including low blood pressure, fainting, electrolyte abnormalities, and acute kidney damage. However, other serious adverse events associated with lower blood pressure, such as slow heart rate and falls with injuries, did not increase in the intensive group. In patients with chronic kidney disease, there was no difference in the rate of serious decline in kidney function between the two blood pressure goal groups.

“The benefits of more intensive blood pressure lowering exceeded the potential for harm, regardless of gender or race/ethnicity,” said study co-author Paul Whelton, M.D., of Tulane University School of Public Health and Tropical Medicine in New Orleans, Louisiana. He is chair of the SPRINT Steering Committee.

In addition to its primary cardiovascular outcome, the study continues to examine kidney disease, cognitive function, and dementia among the SPRINT participants; however, these results are not yet available as additional information will be collected and analyzed over the next year.

“Although the study provides strong evidence that a lower blood pressure target saves lives, patients and their health care providers may want to wait to see how guideline groups incorporate this study and other scientific reports into any future hypertension guidelines. In the meantime, patients should talk to their health care providers to determine whether this lower goal is best for their individual care,” said study co-author Lawrence Fine, M.D., Chief, Clinical Applications and Prevention Branch at NHLBI.

“It’s also important to remember that healthy lifestyle changes can make a difference in controlling high blood pressure,” Dr. Fine added. He emphasized the importance of following a healthy diet, being physically active, maintaining a healthy weight, as well as learning to check your blood pressure.

In addition to primary sponsorship by the NHLBI, SPRINT is co-sponsored by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging.

Part of the National Institutes of Health, the National Heart, Lung, and Blood Institute (NHLBI) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders. The Institute also administers national health education campaigns on women and heart disease, healthy weight for children, and other topics. NHLBI press releases and other materials are available online at http://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health^®

Landmark NIH study shows intensive blood pressure management may save lives

Embargoed for Release:

September 11, 2015, 10:30 AM EDT

Lower blood pressure target greatly reduces cardiovascular complications and deaths in older adults

More intensive management of high blood pressure, below a commonly recommended blood pressure target, significantly reduces rates of cardiovascular disease, and lowers risk of death in a group of adults 50 years and older with high blood pressure. This is according to the initial results of a landmark clinical trial sponsored by the National Institutes of Health called the Systolic Blood Pressure Intervention Trial (SPRINT). The intervention in this trial, which carefully adjusts the amount or type of blood pressure medication to achieve a target systolicpressure of 120 millimeters of mercury (mm Hg), reduced rates of cardiovascular events, such as heart attack and heart failure, as well as stroke, by almost a third and the risk of death by almost a quarter, as compared to the target systolic pressure of 140 mm Hg.

“This study provides potentially lifesaving information that will be useful to health care providers as they consider the best treatment options for some of their patients, particularly those over the age of 50,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute (NHLBI), the primary sponsor of SPRINT. “We are delighted to have achieved this important milestone in the study in advance of the expected closure date for the SPRINT trial and look forward to quickly communicating the results to help inform patient care and the future development of evidence-based clinical guidelines.”

High blood pressure, or hypertension, is a leading risk factor for heart disease, stroke, kidney failure, and other health problems. An estimated 1 in 3 people in the United States has high blood pressure.

The SPRINT study evaluates the benefits of maintaining a new target for systolic blood pressure, the top number in a blood pressure reading, among a group of patients 50 years and older at increased risk for heart disease or who have kidney disease. A systolic pressure of 120 mm Hg, maintained by this more intensive blood pressure intervention, could ultimately help save lives among adults age 50 and older who have a combination of high blood pressure and at least one additional risk factor for heart disease, the investigators say.

The SPRINT study, which began in the fall of 2009, includes more than 9,300 participants age 50 and older, recruited from about 100 medical centers and clinical practices throughout the United States and Puerto Rico. It is the largest study of its kind to date to examine how maintaining systolic blood pressure at a lower than currently recommended level will impact cardiovascular and kidney diseases. NIH stopped the blood pressure intervention earlier than originally planned in order to quickly disseminate the significant preliminary results.

The study population was diverse and included women, racial/ethnic minorities, and the elderly. The investigators point out that the SPRINT study did not include patients with diabetes, prior stroke, or polycystic kidney disease, as other research included those populations.

When SPRINT was designed, the well-established clinical guidelines recommended a systolic blood pressure of less than 140 mm Hg for healthy adults and 130 mm Hg for adults with kidney disease or diabetes. Investigators designed SPRINT to determine the potential benefits of achieving systolic blood pressure of less than 120 mm Hg for hypertensive adults 50 years and older who are at risk for developing heart disease or kidney disease.

Between 2010 and 2013, the SPRINT investigators randomly divided the study participants into two groups that differed according to targeted levels of blood pressure control. The standard group received blood pressure medications to achieve a target of less than 140 mm Hg. They received an average of two different blood pressure medications. The intensive treatment group received medications to achieve a target of less than 120 mm Hg and received an average of three medications.

“Our results provide important evidence that treating blood pressure to a lower goal in older or high-risk patients can be beneficial and yield better health results overall,” said Lawrence Fine, M.D., chief, Clinical Applications and Prevention Branch at NHLBI. “But patients should talk to their doctor to determine whether this lower goal is best for their individual care.”

The study is also examining kidney disease, cognitive function, and dementia among the patients; however, those results are still under analysis and are not yet available as additional information will be collected over the next year. The primary results of the trial will be published within the next few months.

Supplemental Information

What Is High Blood Pressure?: http://www.nhlbi.nih.gov/health/health-topics/topics/hbp
Further information about this trial (NCT01206062) can be found athttps://clinicaltrials.gov/ct2/show/NCT01206062
SPRINT Trial Questions and Answers: http://www.nhlbi.nih.gov/news/spotlight/fact-sheet/systolic-blood-pressure-intervention-trial-sprint-questions-and-answers
SPRINT clinical trial website: https://www.sprinttrial.org/(link is external)
Your Guide to Living Well With Heart Disease:http://www.nhlbi.nih.gov/health/resources/heart/living-with-heart-disease

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A Weighty Anomaly

Spiegelman Sets Out

Spiegelman Simmers

Spiegelman Scales Up

An HFD Promotes Th17 Cell Differentiation and Affects the Expression of Fatty Acid Enzymes in Memory CD4 T Cells In Vivo

Inhibition of ACC1 Function Results in Decreased Th17 Cell Differentiation and Ameliorates the Development of Autoimmune Disease

ACC1 Controls the Differentiation of Th17 Cells Both In Vitro and In Vivo

ACC1 Controls the Function, but Not Expression, of RORγt in Differentiating Th17 Cells

Extrinsic Fatty Acid Supplementation Restored Acaca−/− Th17 Cell Differentiation through the Functional Improvement of RORγt

Obese Subjects Show Upregulation of ACACA and Increased Th17 Cells in CD45RO+ Memory CD4 T Cells

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Irreconciliable Dissonance in Physical Space and Cellular Metabolic Conception

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Extrinsic Fatty Acid Supplementation Restored Acaca^−/− Th17 Cell Differentiation through the Functional Improvement of RORγt

Obese Subjects Show Upregulation of ACACA and Increased Th17 Cells in CD45RO⁺ Memory CD4 T Cells