The Influence of Hyperthyroidism and Hypothyroidism on α and β-Adrenergic Receptor Systems and Adrenergic Responsiveness*

Bilezikian, John P.; Loeb, Jacques

doi:10.1210/edrv-4-4-378

Cited by 349 publications

(161 citation statements)

References 47 publications

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“…Thyroid hormone stimulates basal metabolic rate and adaptive thermogenesis. Hyperthyroidism amplifies catecholamine-stimulated lipolysis and increases thermogenesis and oxygen consumption in adipose tissue (1)(2)(3). Hypothyroidism reduces the response to catecholamines and increases energy-saving anabolic activity in adipose tissue (4).…”

mentioning

confidence: 99%

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

Liu

Schultz

Brent

2003

Journal of Biological Chemistry

150

102

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Thyroid hormone has profound effects on metabolic homeostasis, regulating both lipogenesis and lipolysis, primarily by modulating adrenergic activity. We generated mice with a point mutation in the thyroid hormone receptor ␣ (TR␣) gene producing a dominant-negative TR␣ mutant receptor with a proline to histidine substitution (P398H). The heterozygous P398H mutant mice had a 3.4-fold (p < 0.02) increase in serum thyrotropin (TSH) levels. Serum triiodothyronine (T3) and thyroxine (T4) concentrations were slightly elevated compared with wild-type mice. The P398H mice had a 4.4-fold increase in body fat (as a fraction of total body weight) (p < 0.001) and a 5-fold increase in serum leptin levels (p < 0.005) compared with wild-type mice. A 3-fold increase in serum fasting insulin levels (p < 0.002) and a 55% increase in fasting glucose levels (p < 0.01) were observed in P398H compared with wild-type mice. There was a marked reduction in norepinephrine-induced lipolysis, as reflected in reduced glycerol release from white adipose tissue isolated from P398H mice. Heart rate and cold-induced adaptive thermogenesis, mediated by thyroid hormone-catecholamine interaction, were also reduced in P398H mice. In conclusion, the TR␣ P398H mutation is associated with visceral adiposity and insulin resistance primarily due to a marked reduction in catecholamine-stimulated lipolysis. The observed phenotype in the TR␣ P398H mouse is likely due to interference with TR␣ action as well as influence on other metabolic signaling pathways. The physiologic significance of these findings will ultimately depend on understanding the full range of actions of this mutation.Thyroid hormone plays a central role in metabolic homeostasis. Thyroid hormone stimulates basal metabolic rate and adaptive thermogenesis. Hyperthyroidism amplifies catecholamine-stimulated lipolysis and increases thermogenesis and oxygen consumption in adipose tissue (1-3). Hypothyroidism reduces the response to catecholamines and increases energy-saving anabolic activity in adipose tissue (4).Thyroid hormone has long been recognized to augment adrenergic activity, and influences adrenergic signaling at multiple levels. Catecholamines bind at least five subtypes of adrenergic receptors (␣1, ␣2, ␤1, ␤2, and ␤3) that are expressed in fat cells and are coupled with the adenylylcyclase system to activate (via ␤ receptors) or inhibit (via ␣2 receptor) the cAMPactivated hormone-sensitive lipase (HSL) 1 (5-9). Reduced catecholamine-stimulated lipolysis in hypothyroidism is thought to be due to a reduced number of ␤-adrenergic receptors (␤1 and ␤2) in fat cells (4, 10 -13), reduced interaction with G s , and enhanced G i protein interaction via ␣2-adrenergic receptorcoupled stimulation (14). Additionally, hypothyroidism is associated with low intracellular levels of protein kinase, known to phosphorylate and activate HSL (2,12,13). No significant alteration of ␣2-adrenergic receptor number has been found in fat cells isolated from either hypo-or hyperthyroid animals (6).The two majo...

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mentioning

confidence: 99%

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

Liu

Schultz

Brent

2003

Journal of Biological Chemistry

150

102

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“…Stare and lid lag are also known to occur in hyperthyroidism, possibly mediated by increased alpha-adrenergic receptors in peri-ocular tissue [5]. Subclinical hyperthyroidism presents much more vaguely with nonspecific complaints, if any at all.…”

Section: Discussionmentioning

confidence: 99%

De novo coronary artery disease in graves’ disease. coincidence?

Shahsavari

Zoll

2018

Journal of Community Hospital Internal Medicine Perspectives

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Hyperthyroidism is associated with increased risk of cardiovascular conditions. We report a case of a 50-year-old woman with no prior cardiac history who presented to the emergency department with shortness of breath, chest pain, lower extremity swelling, and generalized fatigue. She was found to have Graves’ Disease (GD) and extensive coronary artery disease (CAD), suggesting the possibility of increased risk of de novo CAD in patients with GD in the absence of other risk factors.

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“…Recent developments of highly specific radioligands, by means of which a-adrenergic and P-adrenergic receptors could be identified directly, has promoted studies on the effect of thyroid hormones o n E a n d /3 receptors in rat liver (for a review see [5]). T h e d a t a indicate a thyroid-hormone-mediated decrease in the number of x and /3 receptors.…”

Section: Discussionmentioning

confidence: 99%

“…However, thyroid hormone injection is associated with (a) alterations in the response to other hormones (e.g. catecholamines [5]), (b) increases in circulating glucagon [6], and elevation in tissue content of CAMP [6]. In fact, using thc isolated perfused liver the effect of T3 was found to be reduced to only a small increase in the rate of PEPck synthesis [7].…”

mentioning

confidence: 99%

Permissive action of thyroid hormones in the cAMP‐mediated induction of phosphoenol pyruvate carboxykinase in hepatocytes in culture

Süssmuth

Höppner

Seitz

1984

European Journal of Biochemistry

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Thyroid hormones are known to stimulate in vivo the synthesis of several liver proteins. In order to determine their role in the regulation of important hepatic proteins at the cell level, the effect of T3 on the induction of the glucoregulatory enzyme phosphoenolpyruvate carboxykinase (PEPck) was investigated in cultured hepatocytes. The cells were isolated from adult hypothyroid rats and exposed to a chemically defined medium, devoid of serum supplement and hormone-free over a period of 48 h.(a) Addition of T3 to the medium had only a minor effect on PEPck induction. (b) Dibutyryladenosine 3',5'-monophosphate (Bt,cAMP) or epinephrine provoked significant increase in PEPck synthesis within 4-6 h. (c) Simultaneous addition of T3 was found significantly to promote the Bt,cAMP-mediated enzyme induction. (d) Physiological concentrations of T3 (10 pM to 1 nM) were found to be effective in enhancing this CAMP-mediated signal. (e) Exposure of the cells to T3 for only 90 min, 16 h prior to addition of Bt,cAMP was nearly as effective as continuous exposure to T3 in enhancing the CAMP-effect on PEPck synthesis. (f) In contrast, no effect of T3 on the Bt,cAMP-induced tyrosine-aminotransferase activity could be detected.It is concluded that the role of T3 on the CAMP-elicited PEPck synthesis is selective, rapid, primarily permissive and significant within the physiological range of the hormone. In addition, these data indicate that such hepatocyte cultures prepared from hypothyroid rats are ideally suited to the analysis of the regulatory role of thyroid hormones on specific gene expression.The synthesis of hepatic PEPck, the rate-limiting enzyme for gluconeogenesis, is under hormonal control by glucocorticoids, glucagon and catecholamines (for a review see [I]). In addition, thyroid hormone injection in vivo significantly enhances PEPck activity [2, 31 as a consequence of a concomitant acceleration in enzyme synthesis [4]. However, thyroid hormone injection is associated with (a) alterations in the response to other hormones (e.g. catecholamines [5]), (b) increases in circulating glucagon [6], and elevation in tissue content of CAMP [6]. In fact, using thc isolated perfused liver the effect of T3 was found to be reduced to only a small increase in the rate of PEPck synthesis [7]. Recent improvements in the use of isolated hepatocytes in culture provide an excellent tool with which to investigate the long-term effects of thyroid hormones on regulating the synthesis of important proteins. We, therefore, investigated the effect of T3 and its interaction with CAMP and epinephrine in the induction of PEPck in isolated hepatocytes from hypothyroid rats incubated in a chemically defined medium.Our results demonstrate a rapid and permissive effect of thyroid hormones at their physiological, circulating concentrations on the epinephrine-induced and CAMP-induced PEPck synthesis.Abbrcviutions. Bt,cAMP, N ',02'-dibutyryladenosine 3',5'-monophosphate; T3, ~-3,3',5-triiodothyronine; PEPck. phosphoenolpyruvate carboxy kinase.Enzymev. Ty...

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The Influence of Hyperthyroidism and Hypothyroidism on α and β-Adrenergic Receptor Systems and Adrenergic Responsiveness*

Cited by 349 publications

References 47 publications

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

A Thyroid Hormone Receptor α Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice

De novo coronary artery disease in graves’ disease. coincidence?

Permissive action of thyroid hormones in the cAMP‐mediated induction of phosphoenol pyruvate carboxykinase in hepatocytes in culture

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