Adrenergic activation of triiodothyronine production in brown adipose tissue
TL;DR: It is reported here that both noradrenaline and cold exposure increase BAT 5′D-II through α1-adrenergic receptors, whereas depletion of catecholamines with α-methyl-p-tyrosine (MPT) prevents the effect of cold but not that of nor adrenaline.
Abstract: There are several mechanisms by which homeothermic animals increase heat production, including shivering, sympathetic nervous system activation and stimulation of thyroid hormone secretion. Studies in rats have shown that increased sympathetic activity causes increased heat production in brown adipose tissue (BAT) after cold exposure or food ingestion1–3. Acute cold exposure also increases circulating thyroid hormones4 which in turn stimulate cellular metabolism through induction5 of various enzymes. Most metabolic effects of thyroxine (T4) are thought to be due to the triiodothyronine (T3) which is produced from T4 by a process of 5′ monodeiodination. There are two enzymes responsible for this reaction6–8: type I, or propylthiouracil (PTU)-sensitive iodothyronine deiodinase (5′D-I), which is reduced in hypothyroidism, stimulated in hyperthyroidism and probably provides most of the circulating T3 in the adult rat9. Type II 5′-deiodinase (5′D-II) is characteristic of brain and pituitary, is increased by thyroidectomy, is not inhibited by PTU and provides 50–80% of the intraceUular T3 in these two tissues. Recently, 5′D-II activity was identified in interscapular BAT10. As the sympathetic nervous system influences the metabolic activation of BAT, we have studied the effects of noradrenaline and acute cold exposure on BAT 5′D-II. We report here that both noradrenaline and cold exposure increase BAT 5′D-II through α1-adrenergic receptors, whereas depletion of catecholamines with α-methyl-p-tyrosine (MPT) prevents the effect of cold but not that of noradrenaline. These results suggest that the sympathetic nervous system may increase T3 production in rats by stimulating BAT 5′D-II. By increasing metabolic rate, this rise in T3 would enhance the thermogenic response to sympathetic stimulation.
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TL;DR: The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.
Abstract: Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...
5,470 citations
TL;DR: This review presents the major advances in knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.
Abstract: Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.
1,856 citations
TL;DR: The goal of this review is to place the exciting advances that have occurred in understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context.
Abstract: The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T3 production. We discuss the pathological role of D3 overexpression causing “consumptive hypothyroidism” as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium. (Endocrine Reviews 23: 38–89, 2002)
1,670 citations
TL;DR: The mechanisms used by homeothermic species to generate more heat and their regulation largely by thyroid hormone and the sympathetic nervous system are reviewed, finding that thyroid hormone plays a critical role in modulating the amount of the active TH, T(3), in BAT, thereby modulated the responses to SNS.
Abstract: Increased heat generation from biological processes is inherent to homeothermy. Homeothermic species produce more heat from sustaining a more active metabolism as well as from reducing fuel efficie...
599 citations
Cites background from "Adrenergic activation of triiodothy..."
...The discovery of type II iodothyronine 5 -deiodinase (D2) in BAT and its stimulation by the SNS (146, 216) allowed the demonstration of how important BAT FcT is in cold adaptation and how important TH is for its activation....
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TL;DR: It is reported that despite a normal plasma 3,5,3'-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2(-/-)) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss.
Abstract: Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue (BAT). Here we report that despite a normal plasma 3,5,3'-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2(-/-)) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss. This occurs despite normal basal mitochondrial uncoupling protein 1 (UCP1) concentration. In Dio2(-/-) brown adipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced increases in lipolysis, UCP1 mRNA, and O(2) consumption are all reduced due to impaired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies suggest that UCP1 is primarily dependent on thyroid hormone receptor beta (TR beta) while the normal sympathetic response of brown adipocytes requires TR alpha. Intracellularly generated T3 may be required to saturate the TR alpha, which has an approximately fourfold lower T3-binding affinity than does TR beta. Thus, D2 is an essential component in the thyroid-sympathetic synergism required for thermal homeostasis in small mammals.
467 citations
Cites background from "Adrenergic activation of triiodothy..."
...This is explained by the high D2 activity in hypothyroid BAT, which catalyzes the activation of T4 to T3 (5, 11)....
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...The norepinephrine-induced (NEinduced) increase in cAMP rapidly activates lipolysis, initiating mitochondrial heat production, and increases intracellular thyroxine (T4) activation to 3,5,3′-triiodothyronine (T3) via the type 2 iodothyronine deiodinase (D2) (5)....
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References
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TL;DR: Measurement of energy balance during voluntary over-eating in rats unequivocally establishes the quantitative importance of diet-induced thermogenesis in energy balance and suggests that this tissue may determine metabolic efficiency and resistance to obesity.
Abstract: Measurement of energy balance during voluntary overeating in rats unequivocally establishes the quantitative importance of diet-induced thermogenesis in energy balance. Like cold-induced thermogenesis, this form of heat production involves changes in the activity of the sympathetic nervous system and brown adipose tissue which suggest that this tissue may determine metabolic efficiency and resistance to obesity.
1,432 citations
TL;DR: Flow to heart and to muscles involved in respiratory movements was two to five times greater during calorigenesis and flow to most other tissues and organs increased or decreased by less than 40%.
Abstract: Cardiac output (CO) and the fractional distribution (FD) of γ-labeled plastic microspheres (15 ± 5 μm) injected into the left ventricle were used to calculate blood flow to organs and tissues of ba...
644 citations
TL;DR: ThyroXINE (T4), measured as protein-bound iodine, was the first hormone to be quantitated in human serum, and it was possible to demonstrate clear relationships between circulating T4 concentrations and many of the physiological manifestations of thyroid hormone excess or deficiency.
Abstract: THYROXINE (T4), measured as protein-bound iodine, was the first hormone to be quantitated in human serum. As a consequence, it was possible to demonstrate clear relationships between circulating T4 concentrations and many of the physiological manifestations of thyroid hormone excess or deficiency. In 1952, 3,5,3′-triiodothyronine (T3) was identified in human plasma and metabolic studies in man soon led to the realization that this hormone was 3–4 times as potent metabolically as T4 (1–4). At that time, the question was first raised as to whether T4 or T3 was the “active” thyroid hormone (3). This question became even more pertinent when it was suggested first in 1955 (5) and shown conclusively in 1970 that T4 could be converted to T3 by peripheral human tissues (6, 7). These studies were made possible by the development of methods for quantitating T3 in human serum, initially by competitive protein binding techniques, followed soon thereafter by specific and sensitive RIAs.
534 citations
TL;DR: In a given tissue, alterations in the total number of receptor sites has not been shown to be useful as an index of thyroid hormone response, and local modulation of the response to the triiodothyronine receptor complex by a variety of factors other than triiod Timothyronine may be carried out at a postreceptor level.
Abstract: A large body of circumstantial evidence suggests that the basic unit of thyroid hormone action is the triiodothyronine nuclear receptor complex. This complex stimulates the formation, directly or indirectly, of a diversity of messenger RNA (mRNA) sequences. A generalized increase in mRNA as well as a disproportionate increase in a limited number of RNA sequences have been demonstrated. Regulation of thyroid hormone effects may be carried out largely at a local cellular level. Highly selective alterations in sensitivity to the triiodothyronine nuclear receptor complex may occur at specific target genes. Metabolic factors and hormones participate in such regulation. In a given tissue, alterations in the total number of receptor sites has not been shown to be useful as an index of thyroid hormone response, and local modulation of the response to the triiodothyronine receptor complex by a variety of factors other than triiodothyronine may be carried out at a postreceptor level.
494 citations
TL;DR: It is apparent from these studies that the caloric content as well as the composition of the diet, specifically, the carbohydrate content, can be important factors in regulating the peripheral metabolism of thyroid hormones.
Abstract: Diet-induced alterations in thyroid hormone concentrations have been found in studies of long-term (7 mo) overfeeding in man (the Vermont Study). In these studies of weight gain in normal weight volunteers, increased calories were required to maintain weight after gain over and above that predicted from their increased size. This was associated with increased concentrations of triiodothyronine (T3). No change in the caloric requirement to maintain weight or concentrations of T3 was found after long-term (3 mo) fat overfeeding. In studies of short-term overfeeding (3 wk) the serum concentrations of T3 and its metabolic clearance were increased, resulting in a marked increase in the production rate of T3 irrespective of the composition of the diet overfed (carbohydrate 29.6 +/- 2.1 to 54.0 +/- 3.3, fat 28.2 +/- 3.7 to 49.1 +/- 3.4, and protein 31.2 +/- 2.1 to 53.2 +/- 3.7 microgram/d per 70 kg). Thyroxine production was unaltered by overfeeding (93.7 +/- 6.5 vs. 89.2 +/- 4.9 microgram/d per 70 kg). It is still speculative whether these dietary-induced alterations in thyroid hormone metabolism are responsible for the simultaneously increased expenditure of energy in these subjects and therefore might represent an important physiological adaptation in times of caloric affluence. During the weight-maintenance phases of the long-term overfeeding studies, concentrations of T3 were increased when carbohydrate was isocalorically substituted for fat in the diet. In short-term studies the peripheral concentrations of T3 and reverse T3 found during fasting were mimicked in direction, if not in degree, with equal or hypocaloric diets restricted in carbohydrate were fed. It is apparent from these studies that the caloric content as well as the composition of the diet, specifically, the carbohydrate content, can be important factors in regulating the peripheral metabolism of thyroid hormones.
262 citations