![]() ![]() Thyroid hormone receptor signaling is required for the normal development of PBN neurons linking thyroid hormone to cardiac and temperature regulation. A, parvalbuminergic neurons (PBN): PBN are a population of newly discovered neurons in the anterior hypothalamus that are directly linked to the regulation of cardiovascular function, including heart rate, blood pressure, and body temperature. The monocarboxylate transporter 8 (MCT8) is required for T 3 transport into the pituitary and hypothalamus. Hypothalamic-Pituitary-Thyroid axis: thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) respond primarily to circulating serum T 4, converted in the hypothalamus and pituitary to T 3 by the 5′-deiodinase type 2 (D2). Overview of sites of thyroid hormone regulation of metabolism. We will conclude with the application of these common mechanisms to therapeutic targets. The themes among the interacting TH metabolic pathways include the influence of nutrient feedback, through nuclear receptor crosstalk and epigenetic modifications of histones, the impact of adrenergic signaling, and local ligand availability ( Table 2). This review will examine the various sites of TH action and mechanisms that mediate metabolic regulation, focusing on the interaction among the pathways that regulate lipid and carbohydrate metabolism, and the balance of energy storage and energy expenditure. ![]() These include the molecular mechanisms of TH action ( 28, 40), lipid regulation ( 270), cross-talk with nuclear receptors ( 157), the role of corepressors in metabolic regulation ( 185), thyroid hormone adrenergic interactions ( 233), facultative thermogenesis ( 229), and the metabolic influences on central regulation of TH ( 117, 163). TH regulates metabolism primarily through actions in the brain, white fat, brown fat, skeletal muscle, liver, and pancreas.Ī number of recent reviews have focused on specific actions of TH in metabolic regulation ( Figure 1, Table 1). TH influences key metabolic pathways that control energy balance by regulating energy storage and expenditure ( 40, 127, 157). TH stimulates both lipogenesis and lipolysis, although when TH levels are elevated, the net effect is fat loss ( 191). Conversely, hypothyroidism, reduced thyroid hormone levels, is associated with hypometabolism characterized by reduced resting energy expenditure, weight gain, increased cholesterol levels, reduced lipolysis, and reduced gluconeogenesis ( 27). Hyperthyroidism, excess thyroid hormone, promotes a hypermetabolic state characterized by increased resting energy expenditure, weight loss, reduced cholesterol levels, increased lipolysis, and gluconeogenesis ( 26, 184). It is well established that thyroid hormone status correlates with body weight and energy expenditure ( 80, 127, 143). Thyroid hormone (TH) regulates metabolic processes essential for normal growth and development as well as regulating metabolism in the adult ( 28, 40, 189). Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets. ![]() The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. 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. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. 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 thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. Local activation of thyroxine (T 4), to the active form, triiodothyronine (T 3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. ![]()
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