Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Thyroid hormone (TH) signaling plays an important role in development and adult life. Many organisms may have evolved under selective pressure of exogenous TH, suggesting that thyroid hormone signaling is phylogenetically older than the systems that regulate their synthesis. Therefore, the negative feedback system by TH itself was probably the first mechanism of regulation of circulating TH levels. Neuroendocrine signalling allows for integration of function of distinct tissues in complex organisms, leading to coordinated response to a given challenge and increased fitness for that organism. The hypothalamic-pituitary-thyroid (HPT) axis is a classical example of how a neuroendocrine system regulates distinct functions of an organism both during development and in adult life in response to a variety of challenges, presumably improving its chance of success. For instance, thyroid function and circulating thyroid hormones (TH) levels change in response to some of the most demanding conditions an adult organism may be exposed to, such as reduced food availability, decreased environmental temperature, and illness. Interestingly, the presence of TH precedes the thyroid itself, and exogenous TH has major effects even on organisms that lack thyroid-like structures. Indeed, it has been hypothesized that some invertebrates may obtain TH from diet, suggesting that TH signalling is phylogenetically older than the systems that regulate their synthesis in multicellular organisms. Thus, it is tempting to hypothesize that the regulatory mechanisms that control TH synthesis evolved under the selective pressure of TH action. Indeed, it is well known that an excess of TH suppress, whereas the absence stimulates their own synthesis in a variety of organisms, including humans. Thus, it is plausible to assume that a negative feedback system was probably the first mechanism of regulation of TH levels. However, through evolution, new pathways emerged to control TH levels. In humans and other vertebrates, it is well known that TH negatively regulates its own production through central actions that modulate the hypothalamic-pituitary-thyroid (HPT) axis. Indeed, primary hypothyroidism leads to the up-regulation of the genes encoding many key players in the HPT axis, such as TRH, type 2 deiodinase (dio2), pyroglutamyl peptidase II (PPII), TRH receptor 1 (TRHR1), and the TSH a- and b-subunits. However, in many physiological circumstances, the activity of the HPT axis is not always a function of circulating TH concentrations. Indeed, circadian changes in the HPT axis activity are not a consequence of oscillation in circulating TH levels. Similarly, during reduced food availability, several components of the HPT axis are down-regulated even in the presence of lower circulating TH levels, suggesting the presence of a regulatory pathway hierarchically higher than the feedback system.
Regulation of the HPT axis is complex, and every year new advances in the area are made. However, it is far from fully understanding its control. Undoubtedly, the negative feedback imposed by TH plays a role in the regulation of the HPT axis, but there are clearly other key pathways that are working to keep TH levels adequate. Indeed, under physiological conditions, feedback regulation seems to play a less relevant role when compared with conditions where primary dysfunction of the thyroid gland is present. It is true that in some situations (e.g. starvation), changes in central action of TH might cause a shift in the set point of the HPT axis. However, the signaling pathways driving these putative set-point-modifying phenomena need to be elucidated. For instance, it is known that the coregulators SRC-1 and NCoR1 (nuclear receptor corepressor 1) control the action of TH also on negatively regulated genes and those changes in their expression/ action shift the set point of the HPT axis. However, it remains to be demonstrated how this is orchestrated in physiological conditions and what would be driving these modifications. Neural circuitries regulate thyroid activity through the control of TRH release in the median eminence, and this seems to be especially relevant in the control of circadian rhythm and in response to both fasting and reduced environmental temperature. Interestingly, during those situations, changes in circulating TH levels do not elicit a counter-regulatory response of the hypothalamic-pituitary axis. Therefore, it is tempting to assume the existence of regulatory mechanisms able to override negative feedback regulation. Strikingly, some of these pathways may be controlling distinct responses to a common stressor, such as during restricted food availability. In that situation, NPY (neuropeptide Y) signaling plays a crucial role in the control of both food intake and HPT axis activity, suggesting that these pathways may have evolved together as a common energy replenishing response. Taken together, this suggests that the regulation of the HPT axis occurs at multiple levels and is highly integrated with the internal milieu and the external environment.
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Dr. Saha,
Thank you for this post.
Since HPT axis plays a major role in endocrine sysyem involved in Reproduction and in Fertility, may I suggest that you will plan to post on Female model: HRT in Reproduction and Fertility, and
Male model: HRT in Reproduction and Fertility
These two posts will bring many hits, they will enter the 2013 year end e-book
On Endocrinology Genomics and Reproduction Genomics which you will be the EDITOR, of.
Thank you
There is another part of this story that is essential. Patients with Kwashiorkor have impaired thyroid function. This is also a feature of anorexia nervosa. Stress hypermetabolism isn’t to be discounted either.
The thyroid is sensitive to the total body sulfur. Plant foods have a S:N ratio of 1:20 compared with animal sources at 1:12. This puts the vegan at serious risk.
Transthyretin is a transport protein made by the liver that circulates with thyroxine (in addition to and separate fromTBG),. It decreases with the stressed state as the liver reprioritizes synthesis to APRs (acute phase reactants). The importance of TTR is that it is a direct readout of total body sulfur. It has a half-life of roughly 48 h.
Much work has been done in this by Vernon Young (MIT)(deceased), and by Yves Ingenbleek at Univ Louis Pasteur, Strasbourg, Fr, who did the seminal study on Kwashiokor. Later work with Dr. Young established a tie in between TTR and sulfur metabolism by way of methyl-goup donors through S-adenosyl methionine.
Depletion of sulfur is tied to muscle autocatabolism by proteolysis and is central to the protein-energy malnutrition/stress hypermetabolism conundrum.
There is overproduction of cortisol mediated by several cytokines acting on both the adrenal cortex (10) and on the pituitary through hypothalamic CRH with loss of feedback regulation of ACTH production (11). Hypercortisolemia is a major finding observed after surgery (12), sepsis (13), and medical insults (14), usually correlated to the severity of aggression (5) and of complications (15). Rising cortisol values parallel hyperglycemic trends, as an effect of both gluconeogenesis (16) and insulin resistance (17). Working in concert with TNF, glucocorticoids govern the breakdown of muscle mass (18), which is regarded as the main factor responsible for the negative N balance (1,2).
Hyperglucagonemia counteracts the effects of insulin and contributes to the hyperglycemia of injury (19) and sepsis (20). The relative predominance of glucagon over insulin favors the degradation of hepatic glycogen, which is rapidly exhausted, and increases the conversion of N residues from muscle proteolysis for gluconeogenesis (20).
Under normal conditions, GH exerts both lipolytic and anabolic influences in the whole body economy under the dual control of the hypothalamic hormones somatocrinin (GHRH) and somatostatin (SRIH) (28). GH secretion is usually depressed by rising blood concentrations of glucose and free fatty acids (FFAs) but is paradoxically elevated despite hyperglycemia in stressed patients (29). GH, the fourth mediator of counterregulation, maintains its insulin opposing lipolytic activity (28,30) through the activation of the hormone-sensitive lipase found in adipocytes (31).
The acute stage of stress is associated with the onset of a low T3 syndrome typically delineated by the drop of both total (TT3) and free (FT3) triiodothyronine plasma levels in the subnormal range. In contrast, both total (TT4) and free (FT4) thyroxine values usually remain within normal ranges with declining trends observed for TT4 and rising tendencies for FT4 (44). This latter free compound is regarded as the sensor reflecting the actual thyroid status and governing the release of TSH (44) whereas FT3 works as the active hormonal mediator at nuclear receptor level (45). The maintenance of an euthyroid sick syndrome is compatible with the downregulation of most metabolic and energetic processes in healthy tissues (46).
The liver is situated at the intersection of healthy and inflamed territories. On the one hand, the organ actively participates to the preservation of the overall body economy by the catabolic drive of energy reserves towards lipid dependency. On the other hand, cytokines compel the organ to redress the balances between body protein pools and synthetic / functional processes in aid of defense systems and wound healing. Contrary to the rest of the body, energy requirements of the inflamed territory are primarily fulfilled by anaerobic glycolysis (52), an effect triggered by the inhibition of key enzymes of carbohydrate metabolism, notably pyruvate dehydrogenase (53). This non-oxidative combustion of glucose reveals low conversion efficiency but offers the major advantage to maintain, in the context of hyperglycemia, fuel provision to poorly irrigated and/or edematous tissues.
The most fascinating aspects raised by the NDAD concept refer to the divergent and sometimes opposite roles played by some mediators or key compounds in relation with their tissue origin. This is the case for 5’-DA activity, reportedly depressed by cytokines in thyrocytes (49), but exacerbated by the same mediators at hepatocyte level (54,55). This distinct behavior allows the augmented supply of bioactive T3 molecules and the local overstimulation of thyro-dependent processes in an overall economy characterized by thyroid down regulation.
In spite of a turnover rate 4 times more rapid (T ½ : 14 hours) than that of TTR, the TTR-RBP-retinol complex normally fluctuates along preserved 1 : 1 : 1 equimolar ratios. Both clinical (68,78) and experimental (86) studies have shown that TTR secretory rate is the main determinant of RBP blood concentrations, leading to striking evolving similarities. RBP has therefore been propounded as nutritional marker in PEM states (87). Under stressful circumstances, the nadir profile recorded for RBP coincides with that of TTR yielding, here too, a decoupled free ligand pool available to body cells (3). This transitory hyperretinolemic state conforms to the free hormonal theory as the freed ligand may undergo cellular uptake and faster stimulation of retinoid-dependent processes (88) likely to reinforce in several ways the body responses to stress (3).
TTR is crucially involved in the stimulation of T4-dependent processes and indirectly responsible for the enhancement of retinoid pathways (3). The magnitude and duration of these boostering effects are proportionate to the impact of injury, more precisely to the amounts of ligands freed and becoming available for cellular uptake (3). Free cortisol, free thyroxine and free
retinol working alone, synergistically or in succession are shown capable of setting in motion a number of key-enzymes involved in energy metabolism and synthetic pathways (Na+/K+ ATPase, thymidine kinase, protein C kinase, acetylCoA carboxylase, 5’-DA, mannosyltransferases), as well as major APPs controlling defense systems and repair processes (C-reactive protein, fibronectin, orosomucoid, haptoglobin, 2-macroglobulin), mediators and growth factors of utmost biological importance (epidermal growth factor, nerve growth factor, transforming growth factor-, cellular retinol-BP-I, osteocalcin) and cell lines participating to tissue rebuilding (macrophages, fibroblasts, keratinocytes, chondrocytes).
Declared PEM is typically characterized by the fibrotic involution of the thyroid gland, the exhaustion of T4 liver reserves and the lowering of TT4 blood values resulting from depressed biosynthesis of the 3 TH-BPs (28 % of normal for TTR, 53 % for SA, 56 % for TBG) (94). Under these conditions, any aggressive condition superimposed on preexisting PEM entails a further dampened decrement of TTR-RBP concentrations, implying insufficient delivery of both FT4 and free retinol to generate optimal tissue reactions (3).
Our NDAD concept provides a comprehensive and unifying overview of the body responses to stressful stimuli, serving to reconcile the discordant and sometimes contradictory data found in the literature. We assume that the stress reaction always follows similar qualitative avenues in spite of large quantitative discrepancies, depending on the nature and severity of the causal factor – septic, traumatic, toxic, auto-immune, neoplastic. Our NDAD theory suggests that a stressful condition of any cause is basically characterized by the primary surge of cytokine molecules inducing a secondary wave of hormone-like agents critically involved in the adjustment of metabolic requirements of the stressed body (3). Working in concert or antagonistically, these mediators operate along distinct pathways to generate a dichotomous partitioning of the body economy (3). Taken as a whole, healthy tissues are down-regulated and display metabolic needs grounded on lipid dependency whereas the diseased territory disconnected from central regulatory systems manifests up-regulated activities upheld by glycolytic energy supply.
Vegetarian subjects consuming subnormal amounts of methionine (Met) are characterized by subclinical protein malnutrition causing reduction in size of their lean body mass (LBM) best identified by the serial measurement of plasma transthyretin (TTR). As a result, the transsulfuration pathway is depressed at cystathionine-β-synthase (CβS) level triggering the upstream sequestration of homocysteine (Hcy) in biological fluids and promoting its conversion to Met. Maintenance of beneficial Met homeostasis is counterpoised by the drop of cysteine (Cys) and glutathione (GSH) values downstream to CβS causing in turn declining generation of hydrogen sulfide (H2S) from enzymatic sources. The biogenesis of H2S via non-enzymatic reduction is further inhibited in areas where earth’s crust is depleted in elemental sulfur (S8) and sulfate oxyanions. Combination of subclinical malnutrition and S8-deficiency thus maximizes the defective production of Cys, GSH and H2S reductants, explaining persistence of unabated oxidative burden. The clinical entity increases the risk of developing cardiovascular diseases (CVD) and stroke in underprivileged plant-eating populations regardless of Framingham criteria and vitamin-B status. Although unrecognized up to now, the nutritional disorder is one of the commonest worldwide, reaching top prevalence in populated regions of Southeastern Asia. Increased risk of hyperhomocysteinemia and oxidative stress may also affect individuals suffering from intestinal malabsorption or westernized communities having adopted vegan dietary lifestyles.
Both morbid conditions are governed by distinct pathogenic mechanisms leading to the reduction in size of lean body mass (LBM). The liver production of TTR integrates the dietary and stressful components of any disease spectrum, explaining why it is the sole plasma protein whose evolutionary patterns closely follow the shape outlined by LBM fluctuations. Serial measurement of TTR therefore provides unequalled information on the alterations affecting overall protein nutritional status. Recent advances in TTR physiopathology emphasize the detecting power and preventive role played by the protein in hyperhomocysteinemic states, acquired metabolic disorders currently
ascribed to dietary restriction in water-soluble vitamins. Sulfur (S)-deficiency is
proposed as an additional causal factor in the sizeable proportion of hyperhomocysteinemic patients characterized by adequate vitamin intake but experiencing varying degrees of nitrogen (N)-depletion. Owing to the fact that N and S coexist in plant and animal tissues within tightly related concentrations, decreasing LBM as an effect of dietary shortage and/or excessive hypercatabolic losses induces proportionate S-losses. Regardless of water-soluble vitamin status, elevation of homocysteine plasma levels is negatively correlated with LBM reduction and declining TTR plasma levels. These findings occur as the result of impaired cystathionine-b-synthase activity, an enzyme initiating the transsulfuration pathway and whose suppression promotes the
upstream accumulation and remethylation of homocysteine molecules. Under conditions of N- and S-deficiencies, the maintenance of methionine homeostasis indicates high metabolic priority.
Yves Ingenbleek, MD, PhD and Larry Bernstein, MD. THE NUTRITIONALLY-DEPENDENT ADAPTIVE DICHOTOMY (NDAD) AND STRESS HYPERMETABOLISM. « J CLIN LIGAND ASSAY » (out of print)
Yves Ingenbleek, MD, PhD. THE OXIDATIVE STRESS OF HYPERHOMOCYSTEINEMIA RESULTS FROM REDUCED BIOAVAILABILITY OF SULFUR-CONTAINING REDUCTANTS. The Open Clinical Chemistry Journal, 2011, 4, 34-44
Ingenbleek, Y.; Hardillier, E.; Jung, L. Subclinical protein malnutrition is a determinant of hyperhomocysteinemia. Nutrition, 2002, 18, 40-46.
Ingenbleek, Y.; Young, V.R. The essentiality of sulfur is closely related to nitrogen metabolism: a clue to hyperhomocysteinemia. Nutr. Res. Rev., 2004, 17, 135-153.
Yves Ingenbleek. Plasma Transthyretin Reflects the Fluctuations
of Lean Body Mass in Health and Disease. Chapter 20.
Dr. Larry,
Please convert this comment of yours into a stand alone post, with a link to Dr. Saha’s post
Thank you