Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

60.Intermediary Metabolism and the Sympathoadrenal System in Hypothyroidism

J. Enrique Silva

EFFECTS OF THYROID HORMONE ON INTERMEDIARY METABOLISM

Clinicians are familiar with several metabolic abnormalities in hypothyroid patients, most notably increased total and low-density lipoprotein (LDL) cholesterol, hypertriglyceridemia, and reduced metabolic rate, as well as hypoglycemia in more severe hypothyroidism. Such manifestations are the reflection of the diminished or absent cellular levels of thyroid hormone (TH) on various intermediary metabolism pathways. TH has indeed widespread effects on intermediary metabolism. In contrast to other hormones and regulators of metabolism, TH stimulates opposite processes in intermediary metabolism, such as lipolysis and lipogenesis, protein synthesis and degradation, glucose consumption, and glucose production. This augmented substrate cycling may serve two functions, namely, to increase heat generation without causing wasting, as discussed in Chapter 38, as well as to provide fuel and substrates to cope with the acceleration of several biologic processes (growth, remodeling).

Effects of Thyroid Hormone on Protein Metabolism

There is consensus that TH stimulates protein turnover by stimulating both protein synthesis and degradation (1,2). Stimulation of protein synthesis is evident even at low doses of TH in hypothyroid animals and augments in a TH dose-dependent manner (2). Protein degradation is also dose related, and even though it may predominate over the stimulated synthesis in severe thyrotoxicosis, it is in general proportional to synthesis (1,3,4). Circulating levels of amino nitrogen are increased in thyrotoxicosis, but urea synthesis is not increased, indicating that the amino acids from degraded proteins are being reutilized (5). Skeletal muscle is more sensitive to the catabolic effect of thyroid hormone so that even moderate degrees of thyrotoxicosis are associated with some loss of muscle protein (1,4,6), but this effect is usually transient (4). Liver protein content is spared (5).

The biochemical mechanisms whereby TH accelerates protein turnover remain undefined. The increased protein synthesis is probably the reflection of multiple genes whose expression is directly or indirectly stimulated by TH. In rats, growth hormone (GH) gene expression and secretion are highly dependent on TH (7,8), so that a significant fraction of the anabolic response to TH is probably indirectly mediated by growth hormone and insulin-like growthfactor type 1. In humans, the effect of TH on protein synthesis is probably more direct because clinically GH responses to various challenges are only partially, and not universally, impaired in children with hypothyroidism (9). Indeed, the human GH gene promoter is inhibited by TH (10,11), and the variable effect of hypothyroidism on GH secretion is the net result of indirect effects at multiple levels. The TH-induced protein degradation is probably the result of controlled, coordinated activation of various proteases by TH (12). An uncontrolled catabolic state is seen only in severe thyrotoxicosis, and this derives largely from the incapacity of the body to keep up with exaggerated energy demands and increased gluconeogenesis. As expected from the above discussion, protein turnover and amino acid oxidation are reduced in hypothyroidism (13).

Effects of Thyroid Hormone on Carbohydrate Metabolism

Except in severe hypothyroidism, the effects of TH on carbohydrate metabolism are not of major clinical significance. Blood glucose concentration is in general not altered in thyroid dysfunction, but the turnover of glucose is stimulated by TH (14), and this is caused by increased glucose consumption well matched by increased glucose production. Accordingly, it has been previously found that the cycling between glycogenolysis and gluconeogenesis is stimulated by TH (15). Fasting blood glucose is frequently reduced in severe hypothyroidism, and this results largely from impaired gluconeogenesis. A key enzyme in gluconeogenesis is the cytosolic phosphoenolpyruvate carboxykinase (PEPCK), which catalyzes the generation of phosphoenolpyruvate from oxaloacetate. This enzyme is under complex regulation by glucagon, norepinephrine, glucocorticoids, and TH, all of which concur to stimulate activity, as well as by insulin, which represses the activity of the enzyme (16). The PEPCK gene has a complex promoter/enhancer region with regulatory elements for the hormones mentioned above or their intracellular messengers. Triiodothyronine (T3) stimulates the gene directly via its corresponding response element (17) and amplifies the responses of the gene to other stimuli, most notably to cyclic adenosine monophosphate (cAMP) generated in response to glucagon or epinephrine (18), but also enhances the response to glucocorticoids (19). As it occurs with UCP1, and discussed in Chapter 38, the effect of each stimulus is relatively modest, but together their effects are synergistic (T3 and cAMP) or additive (glucocorticoids). This multiplicity of influences allows a more flexible response tuned to the physiologic needs, so that TH will not increase glucose production exaggeratedly in a postprandial status, when signals stimulating gluconeogenesis are low and signals inhibiting glucose production, such as glucose itself and insulin, are high. On the other hand, when this balance fails, such as in diabetes, the stimulatory effect of TH on PEPCK and glucose production resulting from elevated TH levels becomes clinically relevant. In hypopituitarism, the risk for fasting hypoglycemia is enhanced by the concomitant lack of glucocorticoids and TH. In severe primary hypothyroidism, hypoglycemia results from the blunted response of the PEPCK to fasting-induced signals such as glucagon, epinephrine, and glucocorticoids, as well as from the limited supply of gluconeogenic precursors, namely amino acids and glycerol, in turn resulting from reduced protein turnover and limited lipolysis.

Effects of Thyroid Hormone on Lipid Metabolism

As occurs with protein and carbohydrate metabolism, TH stimulates both the de novo synthesis of fatty acids (lipogenesis) and the degradation of lipids (lipolysis and fatty acid oxidation). Lipogenesis is stimulated by T3 mainly in liver, with rather limited effect in white adipose tissue, kidney, and heart, and this is the result of the stimulation of synthesis of key lipogenic enzymes at the transcriptional level (20,21,22). Such enzymes include among others malic enzyme, glucose-6-phosphate dehydrogenase, acetyl CoA carboxylase, and the protein Spot 14, whose stimulation by T3 bears a close relationship with the stimulation of lipogenesis (23). As measured by the incorporation of3H2O into fatty acids, TH stimulates liver lipogenesis 16-fold between the hypothyroid state and a short-term thyrotoxicosis (20). In this transition, liver contribution to total lipogenesis increases by 5% to 50% (20), whereas the relative contribution of white adipose tissue and other organs decreases. Brown adipose tissue global lipogenesis is increased in hypothyroidism, but this is probably due to a complex interaction with the sympathetic nervous system, the activity of which is markedly enhanced in the hypothyroid state (24). If the adrenergic stimulation is prevented, for example by denervation, the stimulatory effect of TH on brown adipose tissue lipogenesis is readily demonstrable (24). Overall lipogenesis increases promptly after T3 injection in rats, which protects the stores of fat before food intake is increased (25). The induction of the hyperthyroid state is immediately associated with increased use of fat as fuel (25), which comes both from increased synthesis in the liver and from hydrolysis of triglycerides (lipolysis) in white adipose tissue. TH stimulates lipolysis indirectly, by enhancing the catecholamine-induced stimulation of the hormone-sensitive lipase in adipose tissue. This results from amplification of the effect of catecholamines at the adrenergic receptor level and, most importantly, at postreceptor levels (see Chapter 38). In rats fasted for 15 hours, white adipose tissue lipolysis is increased. Under such conditions about 55% of the fatty acids are reesterified. TH increases lipolysis and reduces the fraction of fatty acids that is reesterified in situ (26). Interestingly, neither fasting nor TH stimulates reesterification of fatty acids in the liver and its incorporation into very-low-density lipoprotein particles, consistent with the concept that fatty acids are being used as fuel in various tissues. TH actually decreases fatty acid reesterification in liver and increases its oxidation (26).

Although much of the information on the effect of TH on lipid metabolism has been obtained in animal models with short-term experimental thyrotoxicosis, the dose-related manner in which TH stimulates these processes and observations on hypothyroid animals make it reasonable to assume those effects are physiologic. De novo lipogenesis is reduced in hypothyroidism, particularly in the liver, and this is corrected by thyroid hormone (20,27). TH action on lipid metabolism and adipose tissue has also been demonstrated in humans, wherein stimulation of the same relevant genes and lipolysis have been documented (28,29).

There seems to be a distinct difference between rodent models and humans in the response of lipoprotein lipase (LPL) to hypothyroidism. In humans, hypothyroidism is associated with reduced LPL and hepatic lipase activities, both of which respond to TH replacement (30,31,32) and continue to increase, in a T3 concentration-dependent manner in the transition to thyrotoxicosis (33). Such observation may explain the elevation in serum triglyceride levels frequently seen in hypothyroid patients (31,32). In contrast, rat white adipose tissue LPL is inhibited by TH and is, hence, increased in the hypothyroid state (34). TH is believed to induce a messenger RNA (mRNA)–binding protein that inhibits the translation of LPL mRNA upon binding to a specific sequence in the 3′-untranslated region of the LPL mRNA. The low concentration of this protein in hypothyroidism is the cause of the higher LPL abundance and activity (35). LPL mass and activity are much higher in the heart and in oxidative muscle (e.g., soleus) than in the fast twitch muscle extensor digitorum longus (EDL) in euthyroid rats, and hypothyroidism further stimulates activity in heart and soleus but not in EDL (36). It was interesting in these studies that heart, but not EDL or soleus LPL, increased by fasting (36). It has been suggested that the increase in LPL activity in hypothyroid rats results in part from the marked reduction in food intake observed in such rats, because the differences with euthyroid controls are attenuated when these are pair fed with hypothyroid rats (37). Such interspecies difference has no apparent explanation.

Serum cholesterol levels have long been known to be sensitive to thyroid status. Total serum cholesterol is reduced in thyrotoxicosis and increased in hypothyroidism. TH indeed increases cholesterol synthesis, stimulating the rate-limiting enzyme 3-OH-methyl glutaryl CoA reductase (HMG CoA reductase) (38,39). However, the net effect of TH is to reduce cholesterol serum concentrations in a dose-dependent manner (40), which is largely the result of a more vigorous stimulation by TH of the removal of cholesterol by the liver via LDL receptors. TH increases the concentration of these via the stimulation of the expression of sterol regulatory element binding protein-2 (SREBP-2), a transcription factor that enhances LDL gene transcription and expression (see reference 41 and references therein). The stimulation by TH of HMG CoA reductase has a double meaning. All cells produce cholesterol, which is an essential element on plasma membrane. Plasma membrane is a very dynamic cell structure, in constant renovation at rates that are proportional to the metabolic activity of the cells. By stimulating the synthesis of cholesterol (and the other basic components of plasma membrane), TH facilitates its effects and those of other hormones in cell function, remodeling, and differentiation. In addition, cholesterol constitutes the foundation for the synthesis of steroid hormones. From a clinical point of view, higher levels of HMG CoA reductase expand the range where intracellular cholesterol concentration can negatively feed back into its synthesis and cell import of cholesterol. Statins, the collective name of widely used drugs to reduce serum cholesterol levels, work by inhibiting this enzyme. Its effect will depend, therefore, on how much cholesterol synthesis is contributing to its turnover and plasma levels (42).

THE SYMPATHOADRENAL SYSTEM IN HYPOTHYROIDISM

As noted above and in Chapter 38, TH interacts with catecholamines and the sympathoadrenal system (as defined in Chapter 38) at different levels, most notably in the control of metabolism and cardiovascular function. At a central level, TH in general has an inhibitory role over the sympathetic output to the periphery by mechanisms that remain largely undefined. Peripherally and in general terms, TH enhances the responses to catecholamines mediated by β-adrenergic receptors while inhibiting those mediated by α-adrenergic receptors. This dual control allows a synergistic interaction in a controlled manner. Such homeostatic interaction is impaired in hypothyroidism or thyrotoxicosis, as discussed at length in Chapter 38. This chapter briefly summarizes those aspects that relate specifically to catecholamines and hypothyroidism.

Hypothyroidism influences the sympathetic nervous system basically in a direction opposite that of thyrotoxicosis. At the cell and tissue levels, the responses to catecholamines are reduced, whereas the central sympathetic output reaching the tissues is, in general, enhanced. The mechanisms leading to decreased responsiveness or sensitivity to catecholamines vary according to tissue and species. These mechanisms include a reduced number of β-adrenergic receptors and an increased number of α-adrenergic receptors (43); enhanced inhibitory responses to adenosine (44,45,46), probably related to increases in Giα or Gβ protein subunits (47,48,49,50); enhanced phosphodiesterase activity (51); and lack of T3 potentiation of cAMP effects at the gene level (17,52,53). A novel β-adrenergic receptor, the β3-receptor, is receiving much attention (reviewed in reference 54). This receptor is coupled to adenylyl cyclase by Gs-proteins as the β1 and β2 counterparts and is abundantly expressed in brown fat and less so in white adipose tissue. This receptor and its mRNA are increased in rat hypothyroid brown fat and are rapidly reduced by T3, whereas the opposite occurs in white adipose tissue (55), adding another bit of complexity to the intricate thyroid–adrenergic interactions. The α2-adrenergic receptor, which causes inhibition of the cAMP production through coupling to Gi-proteins, is affected little by thyroid dysfunction (56,57).

In contrast to the overall depression of the adrenergic responses at the peripheral level, there is an increase in efferent sympathetic activity reaching virtually every tissue that has been investigated (48,58,59,60,61). Kinetic studies in hypothyroid patients show that the clearance of norepinephrine is not reduced and that the overall production rate of norepinephrine is faster than normal (61,62). Accordingly, plasma levels of norepinephrine are elevated in these patients (63,64,65). Furthermore, the increase in the production rate is selective for norepinephrine because epinephrine turnover is not affected (66). The increase in sympathetic activity appears to be compensatory in nature and may come about in response to the deficient peripheral responses to catecholamines, the thermal stress derived from the lack of the thermogenic effect of thyroid hormone, the reduction in cardiac output, or the lack of T3 in critical regulatory centers of the central nervous system. Some of the abnormalities in the norepinephrine signaling pathway in hypothyroidism may not be caused directly by the lack of thyroid hormone in the tissues but by the increased sympathetic tone; that is, they may represent desensitization. Thus, brown fat–reduced β1- and β2-adrenergic receptors are normalized in athyreotic rats when sympathetic activity is reduced by placing them at 30°C, whereas the number of these receptors decreases in euthyroid rats placed at 4°C (67). Desensitization at a postreceptor level also has been described in brown fat of cold-exposed hamsters (68).

Severely hypothyroid patients may develop hypothermia and myxedema coma after exposure to low environmental temperatures or to medications that compromise heat conservation. Thermogenesis is markedly reduced in these patients: obligatory thermogenesis because of the slow rate of metabolism and facultative thermogenesis because of the diminished response to catecholamines and limited substrate availability due to the lack of thyroid hormone (see Chapter 38 and reference 69 for review). In hypothyroid rats, brown adipose tissue, the main site of facultative thermogenesis, does not respond to cold exposure, exogenous norepinephrine, or nerve stimulation (70,71,72,73,74,75). In humans with hypothyroidism, direct or indirect evidence has been found that metabolic responses to adrenergic stimulation involved in facultative thermogenesis, such as glycogenolysis, lipolysis, gluconeogenesis, and intracellular calcium mobilization, are reduced in hypothyroidism (76,77,78,79,80,81). Reduced heat loss through the skin becomes an essential mechanism for hypothyroid patients to maintain their body temperature. These patients have intense skin and subcutaneous tissue vasoconstriction (82), probably caused by an elevated sympathetic tone (83), increased α1-adrenergic receptors (43), and reduced responses to vasodilatating stimuli (84). These findings suggest that peripheral vasculature is under maximal stimulation, although postreceptor defects in the α1-adrenergic pathway may limit the responses to the enhanced sympathetic input (80,85). In the clinical situation of severe, profound hypothyroidism, therefore, it would seem more prudent to treat the thyroid insufficiency as aggressively as possible, to provide glucose and other supportive treatment, and not to rely on catecholamines to improve the hemodynamic condition or thermogenesis.

In addition to the depressed peripheral vascular response to α1-adrenergic agonists, the responsiveness of the heart to catecholamines is reduced markedly in hypothyroidism. Although the common belief is that this is caused by a reduced number of β-adrenergic receptors in the myocardium (43), there is evidence to indicate important postreceptor defects (45,47,86,87,88). Even though sympathetic stimulation of the heart is increased in hypothyroidism (59,89), the contractility (90) and functional reserve of the heart are severely compromised (91) because of both the direct biochemical consequences of the lack of thyroid hormone and the reduced sympathetic responsiveness. This condition easily can become clinically relevant in cases of bleeding or contraction of the extracellular volume or in cases of rapid reduction of peripheral vascular resistance, as may occur when patients with severe hypothyroidism are rapidly rewarmed. Likewise, volume or pressure overloads may precipitate congestive heart failure. The solutions to such problems are to avoid situations that require important hemodynamic adjustments and to provide thyroid hormone as rapidly as possible. Even though type II 5′-deiodinase mRNA has been identified in the human heart (92), the contribution of this enzyme to nuclear T3 in this organ has not yet been documented, and because thyroxine (T4) to T3 conversion by type I 5′-deiodinase is reduced in hypothyroidism (see Chapter 7), in situations of severely depressed myocardial function, it may be necessary to add small doses of T3 to the initial treatment to accelerate the recovery of the heart (see Chapters 53 and 67).

A number of metabolic abnormalities are also caused in part by the negative effect of hypothyroidism in several signal transduction pathways. Lipolytic responses to catecholamines and glucagon are decreased largely because of postreceptor defects in the cAMP production in animals as well as in humans (51,81,93,94). Glocyogenolysis of muscle and liver also are reduced in part because of defects in the β-adrenergic cAMP pathway and Ca2+ mobilization (80,95). Insulin secretory responses are diminished in part because of defects in the cAMP signaling pathway (96,97). Gluconeogenic responses to glucagon and epinephrine are limited in hypothyroidism in part because of defects in the cAMP cascade and partly because of the lack of thyroid hormone at the level of the PEPCK gene, as discussed above (17,18). As mentioned previously, brown adipose tissue is indeed under maximal adrenergic stimulation in the hypothyroid rat, and yet its responses are depressed dramatically (52,75,98,99). Brown fat lipolytic, respiratory (100), and uncoupling protein responses (101) are also curtailed in brown adipocytes isolated from hypothyroid rats. Despite a clear reduction in β1- and β2-adrenergic receptors (102) and in cAMP accumulation (67,103), these defects do not seem to account for much of the reduced uncoupling protein responses because by the time thyroid hormone administration has completely restored the response of this protein to norepinephrine, neither the receptor number nor cAMP production has been normalized (52,55,67,75). Rather, the dominant defect in hypothyroid brown fat thermogenic responses to adrenergic stimulation seems to reside distal to the generation of cAMP (52,53, 100), pointing again to the physiologic relevance of interactions between cAMP and T3 at levels further beyond, probably the genes themselves. Even though brown adipose tissue may not be as important in human facultative thermogenesis as it is in rodents, these observations underscore the importance of postreceptor defects in the poor responsiveness to catecholamines seen in hypothyroidism.

Thyroid hormone is also important for the development of the sympathetic nervous system. Abundant evidence has been found to show that congenital hypothyroidism results in numerous and ubiquitous abnormalities of the sympathoadrenal system, including the receptors and signaling pathways as well as enzymes involved in the synthesis of catecholamines (104,105,106). Neonatal rat hypothyroidism is associated with reduced β-adrenergic receptor and Gsα proteins, whereas Giα2 and Giα3 proteins are increased and the inotropic responses to isoproterenol are reduced (107). Except for a reduction in β-adrenergic receptor that persists into adulthood, these abnormalities are corrected with treatment and the responses to isoproterenol of the heart of these rats when adults is normal.

REFERENCES

1. Morrison WL, Gibson JN, Jung RT, et al. Skeletal muscle and whole body protein turnover in thyroid disease. Eur J Clin Invest 1988;18:62–68.

2. Brown JG, Millward DJ. Dose response of protein turnover in rat skeletal muscle to triiodothyronine treatment. Biochim Biophys Acta 1983;757:182–190.

3. Tauveron I, Charrier S, Champredon C, et al. Response of leucine metabolism to hyperinsulinemia under amino acid replacement in experimental hyperthyroidism. Am J Physiol 1995;269:E499–E507.

4. Lovejoy JC, Smith SR, Bray GA, et al. A paradigm of experimentally induced mild hyperthyroidism: effects on nitrogen balance, body composition, and energy expenditure in healthy young men. J Clin Endocrinol Metab 1997;82:765–770.

5. Grofte T, Wolthers T, Moller N, et al. Moderate hyperthyroidism reduces liver amino nitrogen conversion, muscle nitrogen contents and overall nitrogen balance in rats. Eur J Clin Invest 1997;27:85–92.

6. Wolman SI, Sheppard H, Fern M, et al. The effect of tri-iodothyronine (T3) on protein turnover and metabolic rate. Int J Obes 1985;9:459–463.

7. Wood DF, Franklyn JA, Docherty K, et al. The effect of thyroid hormones on growth hormone gene expression in vivo in rats. J Endocrinol 1987;112:459–463.

8. Burstein PJ, Draznin B, Johnson CJ, et al. The effect of hypothyroidism on growth, serum growth hormone, the growth hormone–dependent somatomedin, insulin-like growth factor, and its carrier protein in rats. Endocrinology 1979;104:1107–1111.

9. Katz HP, Youlton R, Kaplan SL, et al. Growth and growth hormone. 3. Growth hormone release in children with primary hypothyroidism and thyrotoxicosis. J Clin Endocrinol Metab 1969; 29:346–351.

10. Cattini PA, Anderson TR, Baxter JD, et al. The human growth hormone gene is negatively regulated by triiodothyronine when transfected into rat pituitary cells. J Biol Chem 1986;261:13367–13372.

11. Morin A, Louette J, Voz ML, et al. Triiodothyronine inhibits transcription from the human growth hormone promoter. Mol Cell Endocrinol 1990;71:261–267.

12. Belkhou R, Bechet D, Cherel Y, et al. Effect of fasting and thyroidectomy on cysteine proteinase activities in liver and muscle. Biochim Biophys Acta 1994;1199:195–201.

13. Rochon C, Tauveron I, Dejax C, et al. Response of leucine metabolism to hyperinsulinemia in hypothyroid patients before and after thyroxine replacement. J Clin Endocrinol Metab 2000; 85:697–706.

14. Rochon C, Tauveron I, Dejax C, et al. Response of glucose disposal to hyperinsulinaemia in human hypothyroidism and hyperthyroidism. Clin Sci (Lond) 2003;104:7–15.

15. Shulman GI, Ladenson PW, Wolfe MH, et al. Substrate cycling between gluconeogenesis and glycolysis in euthyroid, hypothyroid, and hyperthyroid man. J Clin Invest 1985;76:757–764.

16. Hanson RW, Reshef L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu Rev Biochem 1997; 66:581–611.

17. Giralt M, Park EA, Gurney AL, et al. Identification of a thyroid hormone response element in the phosphoenolpyruvate carboxykinase (GTP) gene. Evidence for synergistic interaction between thyroid hormone and cAMP cis-regulatory elements. J Biol Chem 1991;266:21991–21996.

18. Hoppner W, Sussmuth W, Seitz HJ. Effect of thyroid state on cyclic AMP-mediated induction of hepatic phosphoenolpyruvate carboxykinase. Biochem J 1985;226:67–73.

19. Hoppner W, Sussmuth W, O'Brien C, et al. Cooperative effect of thyroid and glucocorticoid hormones on the induction of hepatic phosphoenolpyruvate carboxykinase in vivo and in cultured hepatocytes. Eur J Biochem 1986;159:399–405.

20. Blennemann B, Moon YK, Freake HC. Tissue-specific regulation of fatty acid synthesis by thyroid hormone. Endocrinology 1992;130:637–643.

21. Blennemann B, Leahy P, Kim TS, et al. Tissue-specific regulation of lipogenic mRNAs by thyroid hormone. Mol Cell Endocrinol 1995;110:1–8.

22. Feng X, Jiang Y, Meltzer P, et al. Thyroid hormone regulation of hepatic genes in vivo detected by complementary DNA microarray. Mol Endocrinol 2000;14:947–955.

23. Freake HC, Oppenheimer JH. Stimulation of S14 mRNA and lipogenesis in brown fat by hypothyroidism, cold exposure, and cafeteria feeding: evidence supporting a general role for S14 in lipogenesis and lipogenesis in the maintenance of thermogenesis. Proc Natl Acad Sci USA 1987;84:3070–3074.

24. Yeh W-J, Leahy P, Freake HC. Regulation of brown adipose tissue lipogenesis by thyroid hormone and the sympathetic nervous system. Am J Physiol Endocrinol Metab 1993;265:E252–E258.

25. Oppenheimer JH, Schwartz HL, Lane JT, et al. Functional relationship of thyroid hormone-induced lipogenesis, lipolysis and thermogenesis in the rat. J Clin Invest 1991;87:125–132.

26. Kalderon B, Mayorek N, Berry E, et al. Fatty acid cycling in the fasting rat. Am J Physiol Endocrinol Metab 2000;279:E221–E227.

27. Freake HC, Schwartz HL, Oppenheimer JH. The regulation of lipogenesis by thyroid hormone and its contribution to thermogenesis. Endocrinology 1989;125:2868–2874.

28. Viguerie N, Millet L, Avizou S, et al. Regulation of human adipocyte gene expression by thyroid hormone. J Clin Endocrinol Metab 2002;87:630–634.

29. Hellstrom L, Wahrenberg H, Reynisdottir S, et al. Catecholamine-induced adipocyte lipolysis in human hyperthyroidism. J Clin Endocrinol Metab 1997;82:159–166.

30. Pykalisto O, Goldberg AP, Brunzell JD. Reversal of decreased human adipose tissue lipoprotein lipase and hypertriglyceridemia after treatment of hypothyroidism. J Clin Endocrinol Metab 1976;43:591–600.

31. Valdemarsson S, Hedner P, Nilsson-Ehle P. Reversal of decreased hepatic lipase and lipoprotein lipase activities after treatment of hypothyroidism. Eur J Clin Invest 1982;12:423–428.

32. Valdemarsson S, Hansson P, Hedner P, et al. Relations between thyroid function, hepatic and lipoprotein lipase activities, and plasma lipoprotein concentrations. Acta Endocrinol (Copenh) 1983;104:50–56.

33. Lam KS, Chan MK, Yeung RT. High-density lipoprotein cholesterol, hepatic lipase and lipoprotein lipase activities in thyroid dysfunction—effects of treatment. Q J Med 1986;59:513–521.

34. Redgrave TG, Elsegood CL, Mamo JC, et al. Effects of hypothyroidism on the metabolism of lipid emulsion models of triacylglycerol-rich lipoproteins in rats. Biochem J 1991;273: 375–381.

35. Kern PA, Ranganathan G, Yukht A, et al. Translational regulation of lipoprotein lipase by thyroid hormone is via a cytoplasmic repressor that interacts with the 3′ untranslated region. J Lipid Res 1996;37:2332–2340.

36. Ong JM, Simsolo RB, Saghizadeh M, et al. Expression of lipoprotein lipase in rat muscle: regulation by feeding and hypothyroidism. J Lipid Res 1994;35:1542–1551.

37. Hansson P, Nordin G, Nilsson-Ehle P. Influence of nutritional state on lipoprotein lipase activities in the hypothyroid rat. Biochim Biophys Acta 1983;753:364–371.

38. Choi JW, Choi HS. The regulatory effects of thyroid hormone on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Endocr Res 2000;26:1–21.

39. Ness GC, Lopez D, Chambers CM, et al. Effects of L-triiodothyronine and the thyromimetic L-94901 on serum lipoprotein levels and hepatic low-density lipoprotein receptor, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and apo A-I gene expression. Biochem Pharmacol 1998;56:121–129.

40. Bantle JP, Dillmann WH, Oppenheimer JH, et al. Common clinical indices of thyroid hormone action: relationships to serum free 3,5,3′-triiodothyronine concentration and estimated nuclear occupancy. J Clin Endocrinol Metab 1980;50:286–293.

41. Shin DJ, Osborne TF. Thyroid hormone regulation and cholesterol metabolism are connected through sterol regulatory element-binding protein-2 (SREBP-2). J Biol Chem 2003;278: 34114–34118.

42. Ness GC, Chambers CM. Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Proc Soc Exp Biol Med 2000;224:8–19.

43. Bilezikian JP, Loeb JN. The influence of hyperthyroidism and hyperthyroidism on α- and β-adrenergic receptor systems and adrenergic responsiveness. Endocr Rev 1983;4:378–388.

44. Bumgarner JR, Ramkumar V, Stiles GL. Altered thyroid status regulates the adipocyte A1 adenosine receptor-adenylate cyclase system. Life Sci 1989;44:1705–1712.

45. Kaasik A, Seppet EK, Ohisalo JJ. Enhanced negative inotropic effect of an adenosine A1-receptor agonist in rat left atria in hypothyroidism. J Mol Cell Cardiol 1994;26:509–517.

46. Woodward JA, Saggerson ED. Effect of adenosine deaminase, N6-phenylisopropyladenosine and hypothyroidism on the responsiveness of rat brown adipocytes to noradrenaline. Biochem J 1986;238:395–403.

47. Levine MA, Feldman AM, Robishaw JD, et al. Influence of thyroid hormone status on expression of genes encoding G proteins subunits in rat heart. J Biol Chem 1990;265:3553–3560.

48. Michel-Reher MB, Gross G, Jasper JR, et al. Tissue- and subunit-specific regulation of G-protein expression by hypo- and hyperthyroidism. Biochem Pharmacol 1993;45:1417–1423.

49. Orford M, Mazurkiewicz D, Milligan G, et al. Abundance of the alpha-subunits of Gi1, Gi2 and Go in synaptosomal membranes from several regions of the rat brain is increased in hypothyroidism. Biochem J 1991;275:183–186.

50. Rapiejko PJ, Watkins DC, Ros M, et al. Thyroid hormones regulate G-protein β-subunit mRNA expression in vivo. J Biol Chem 1989;264:16183–16189.

51. Goswami A, Rosenberg IN. Effects of thyroid status on membrane-bound low Km cyclic nucleotide phosphodiesterase activities in rat adipocytes. J Biol Chem 1985;260:82–85.

52. Bianco AC, Sheng X, Silva JE. Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis. J Biol Chem 1988;263:18168–18175.

53. Silva JE, Rabelo R. Regulation of the uncoupling protein gene expression. Eur J Endocrinol 1997;136:251–264.

54. Lowell BB, Flier JS. Brown adipose tissue, beta 3-adrenergic receptors, and obesity [Review]. Annu Rev Med 1997;48:307–316.

55. Rubio A, Raasmaja A, Silva JE. Effects of thyroid hormone on norepinephrine signalling in brown adipose tissue. II. Differential effects of thyroid hormone on β3-adrenergic receptors in brown and white adipose tissue. Endocrinology 1995;136:3277–3284.

56. Del Rio G, Zizzo G, Marrama P, et al. Alpha 2-adrenergic activity is normal in patients with thyroid disease. Clin Endocrinol (Oxf) 1994;40:235–239.

57. Richelsen B, Sorensen NS. Alpha 2- and beta-adrenergic receptor binding and action in gluteal adipocytes from patients with hypothyroidism and hyperthyroidism. Metabolism 1987;36:1031–1039.

58. Gripois D, Valens M. Uptake and turnover rate of norepinephrine in interscapular brown adipose tissue of the young rat: influence of hypothyroidism. Biol Neonate 1982;42:113–119.

59. Landsberg L, Axelrod J. Influence of pituitary, thyroid and adrenal hormones on norepinephrine turnover and metabolism in the rat heart. Circ Res 1968;22:559–571.

60. Matsukawa T, Mano T, Gotoh E, et al. Altered muscle sympathetic nerve activity in hyperthyroidism and hypothyroidism. J Auton Nerv Syst 1993;42:171–175.

61. Polikar R, Kennedy B, Ziegler M, et al. Plasma norepinephrine kinetics, dopamine-beta-hydroxylase, and chromogranin-A, in hypothyroid patients before and following replacement therapy. J Clin Endocrinol Metab 1990;70:277–281.

62. Coulombe P, Dussault JH. Catecholamine metabolism in thyroid disease. II. Norepinephrine secretion rate in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 1977; 44:1185–1189.

63. Brown RT, Lakshmanan MC, Baucom CE, et al. Changes in blood pressure and plasma noradrenaline in short-term hypothyroidism. Clin Endocrinol (Oxf) 1989;30:635–638.

64. Coulombe P, Dussault JH, Walker P. Plasma catecholamine concentrations in hyperthyroidism and hypothyroidism. Metabolism 1976;25:973–979.

65. Manhem P, Bramnert M, Hallengren B, et al. Increased arterial and venous plasma noradrenaline levels in patients with primary hypothyroidism during hypothyroid as compared to euthyroid state. J Endocrinol Invest 1992;15:763–765.

66. Coulombe P, Dussault JH, Letarte J, et al. Catecholamine metabolism in thyroid diseases. I. Epinephrine secretion rate in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab 1976;42:125–131.

67. Rubio A, Raasmaja A, Maia AL, et al. Effects of thyroid hormone on norepinephrine signalling in brown adipose tissue. I. β1- and β2-adrenergic receptors and cyclic adenosine monophosphate generation. Endocrinology 1995;136:3267–3276.

68. Svoboda P, Unelius L, Cannon B, et al. Attenuation of Gsa coupling efficiency in brown-adipose-tissue plasma membranes from cold-acclimated hamsters. Biochem J 1993;295:655–661.

69. Silva JE. The thermogenic effect of thyroid hormone and its clinical implications. Ann Intern Med 2003;139:205–213.

70. Bianco AC, Silva JE. Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue. J Clin Invest 1987;79:295–300.

71. Carvalho SD, Kimura ET, Bianco AC, et al. Central role of brown adipose tissue thyroxine 5′deiodinase on thyroid hormone-dependent thermogenic response to cold. Endocrinology 1991;128:2149–2159.

72. Mory G, Ricquier D, Pesquies P, et al. Effects of hypothyroidism on the brown adipose tissue of adult rats: comparison with the effects of adaptation to the cold. J Endocrinol 1981; 91:515–524.

73. Seydoux J, Giacobino J-P, Girardier L. Impaired metabolic response to nerve stimulation in brown adipose tissue of hypothyroid rats. Mol Cell Endocrinol 1982;25:213–226.

74. Triandafillou J, Gwilliam C, Himms-Hagen J. Role of thyroid hormone in cold-induced changes in rat brown adipose tissue mitochondria. Can J Biochem 1982;60:530–537.

75. Silva JE. Full expression of uncoupling protein gene requires the concurrence of norepinephrine and triiodothyronine. Mol Endocrinol 1988;2:706–713.

76. Clausen T, van Hardeveld C, Everts ME. Significance of cation transport in control of energy metabolism and thermogenesis. Physiol Rev 1991;71:733–774.

77. Leijendekker WJ, van Hardeveld C, Elzinga G. Heat production during contraction in skeletal muscle of hypothyroid mice. Am J Physiol 1987;253(part 1):E214–E220.

78. McCulloch AJ, Johnston DG, Baylis PH, et al. Evidence that thyroid hormones regulate gluconeogenesis from glycerol in man. Clin Endocrinol (Oxf) 1983;19:67–76.

79. Sestoft L. Metabolic aspects of the calorigenic effect of thyroid hormone in mammals. Clin Endocrinol (Oxf) 1980;13:489–506.

80. Storm H, van Hardeveld C. Effect of thyroid hormone on intracellular Ca2+ mobilization by noradrenaline and vasopressin in relation to glycogenolysis in rat liver. Biochim Biophys Acta 1985;846:275–285.

81. Wahrenberg H, Wennlund A, Arner P. Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients. J Clin Endocrinol Metab 1994;78:898–903.

82. Vagn NH, Hasselstrom K, Feldt-Rasmussen U, et al. Increased sympathetic tone in forearm subcutaneous tissue in primary hypothyroidism. Clin Physiol 1987;7:297–302.

83. Fagius J, Westermark K, Karlsson A. Baroreflex-governed sympathetic outflow to muscle vasculature is increased in hypothyroidism. Clin Endocrinol (Oxf) 1990;33:177–185.

84. McAllister RM, Grossenburg VD, Delp MD, et al. Effects of hyperthyroidism on vascular contractile and relaxation responses. Am J Physiol 1998;274:E946–E953.

85. Daza FJ, Parrilla R, Martin-Requero A. Influence of thyroid status on hepatic alpha 1-adrenoreceptor responsiveness. Am J Physiol 1997;273:E1065–E1072.

86. Beekman RE, van Hardeveld C, Simonides WS. On the mechanism of the reduction by thyroid hormone of beta-adrenergic relaxation rate stimulation in rat heart. Biochem J 1989;259: 229–236.

87. Daly MJ, Dhalla NS. Alterations in the cardiac adenylate cyclase activity in hypothyroid rat. Can J Cardiol 1985;1:288–293.

88. Zhang Y, Xu K, Han C. Alterations of cardiac α1-adrenoceptor subtypes in hypothyroid rats. Clin Exp Pharmacol Physiol 1997;24:481–486.

89. Tu T, Nash CW. The influence of prolonged hyper- and hypothyroid states on the noradrenaline content of rat tissues and on the accumulation and efflux rates of tritiated noradrenaline. Can J Physiol Pharmacol 1975;53:74–80.

90. Buccino RA, Spann JF Jr, Pool PE, et al. Influence of the thyroid state on the intrinsic contractile properties and energy stores of the myocardium. J Clin Invest 1967;46:1669–1682.

91. Bramnert M, Hallengren B, Lecerof H, et al. Decreased blood pressure response to infused noradrenaline in normotensive as compared to hypertensive patients with primary hypothyroidism. Clin Endocrinol (Oxf) 1994;40:317–321.

92. Salvatore D, Bartha T, Harney JW, et al. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology 1996;137:3308–3315.

93. Milligan G, Saggerson ED. Concurrent up-regulation of guanine-nucleotide-binding proteins Gi1 alpha, Gi2 alpha and Gi3 alpha in adipocytes of hypothyroid rats. Biochem J 1990;270:765–769.

94. Saggerson ED. Sensitivity of adipocyte lipolysis to stimulatory and inhibitory agonists in hypothyroidism and starvation. Biochem J 1986;238:387–394.

95. Chu DT, Shikama H, Khatra BS, et al. Effects of altered thyroid status on beta-adrenergic actions on skeletal muscle glycogen metabolism. J Biol Chem 1985;260:9994–10000.

96. Diaz GB, Paladini AA, Garcia ME, et al. Changes induced by hypothyroidism in insulin secretion and in the properties of islet plasma membranes. Arch Int Physiol Biochim Biophys 1993;101:263–269.

97. Young JB, Landsberg L. Catecholamines and the regulation of hormone secretion [Review]. Clin Endocrinol Metab 1977;6:657–695.

98. Arieli A, Chinet A. Brown adipose tissue heat production in heat acclimated and perchlorate treated rats. Horm Metab Res 1985;17:12–15.

99. Ilyes I, Yahata T, Stock M. Brown adipose tissue cell respiration in hypo- and hyperthyroidism after stimulation with selective and non selective beta-adrenergic agonists. Acta Biol Hungar 1991;42:345–355.

100. Sundin U, Mills I, Fain JN. Thyroid-catecholamine interactions in isolated brown adipocytes. Metabolism 1984;33:1028–1033.

101. Bianco AC, Kieffer JD, Silva JE. Adenosine 3′,5′-monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes. Endocrinology 1992;130:2625–2633.

102. Revelli JP, Pescini R, Muzzin P, et al. Changes in β1- and β2-adrenergic receptor mRNA levels in brown adipose tissue and heart of hypothyroid rats. Biochem J 1991;277:625–629.

103. Raasmaja A, Larsen PR. α1- and β-adrenergic agents cause synergistic stimulation of the iodothyronine deiodinase in rat brown adipocytes. Endocrinology 1989;125:2502–2509.

104. Blouquit MF, Gripois D. Norepinephrine and dopamine content in the brown adipose tissue of developing eu- and hypothyroid rats. Horm Metab Res 1991;23:326–328.

105. Blouquit MF, Gripois D. Activity of enzymes involved in norepinephrine biosynthesis in the brown adipose tissue of the developing rat. Influence of hypothyroidism. Horm Metab Res 1990;22:423–425.

106. Diarra A, Lefauconnier JM, Valens M, et al. Tyrosine content, influx and accumulation rate, and catecholamine biosynthesis measured in vivo, in the central nervous system and in peripheral organs of the young rat: influence of neonatal hypo- and hyperthyroidism. Arch Int Physiol Biochim 1989;97:317–332.

107. Novotny J, Bourova L, Malkova O, et al. G proteins, β-adrenoreceptors and β-adrenergic responsiveness in immature and adult rat ventricular myocardium: influence of neonatal hypo- and hyperthyroidism. J Mol Cell Cardiol 1999;31:761–772.