Thyroid Hormone Regulation and Insulin Resistance: Insights From Animals Naturally Adapted to Fasting

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Abstract

The contribution of thyroidal status in insulin signaling and glucose homeostasis has been implicated as a potential pathophysiological factor in humans, but the specific mechanisms remain largely elusive. Fasting induces changes in both thyroid hormone secretion and insulin signaling. Here, we explore how mammals that undergo natural, prolonged bouts of fasting provide unique insight into evolved physiological adaptations that allow them to tolerate such conditions despite intermittent states of reversible insulin resistance. Such insights from nature may provide clues to better understand the basis of thyroidal involvement in insulin dysregulation in humans.

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Rashmi S Mullur, Yan-Yun Liu, Gregory A Brent (2014)

Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.

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Domenico Salvatore, Warner Simonides, Monica Dentice … (2014)

Thyroid hormone signalling regulates crucial biological functions, including energy expenditure, thermogenesis, development and growth. The skeletal muscle is a major target of thyroid hormone signalling. The type 2 and 3 iodothyronine deiodinases (DIO2 and DIO3, respectively) have been identified in skeletal muscle. DIO2 expression is tightly regulated and catalyses outer-ring monodeiodination of the secreted prohormone tetraiodothyronine (T4) to generate the active hormone tri-iodothyronine (T3). T3 can remain in the myocyte to signal through nuclear receptors or exit the cell to mix with the extracellular pool. By contrast, DIO3 inactivates T3 through removal of an inner-ring iodine. Regulation of the expression and activity of deiodinases constitutes a cell-autonomous, pre-receptor mechanism for controlling the intracellular concentration of T3. This local control of T3 activity is crucial during the various phases of myogenesis. Here, we review the roles of T3 in skeletal muscle development and homeostasis, with a focus on the emerging local deiodinase-mediated control of T3 signalling. Moreover, we discuss these novel findings in the context of both muscle homeostasis and pathology, and examine how skeletal muscle deiodinase activity might be therapeutically harnessed to improve satellite-cell-mediated muscle repair in patients with skeletal muscle disorders, muscle atrophy or injury.

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Suzy Bianco, Theresa Kim (2006)

The deiodinases activate or inactivate thyroid hormone, and their importance in thyroid hormone homeostasis has become increasingly clear with the availability of deiodinase-deficient animals. At the same time, heightened interest in the field has been generated following the discovery that the type 2 deiodinase can be an important component in both the Hedgehog signaling pathway and the G protein-coupled bile acid receptor 1-mediated (GPBAR1-mediated) signaling cascade. The discovery of these new roles for the deiodinases indicates that tissue-specific deiodination plays a much broader role than once thought, extending into the realms of developmental biology and metabolism.