Thyroid hormone regulation of metabolism

Abstract

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.

FIGURE 1.

Overview of sites of thyroid hormone regulation of metabolism. Hypothalamic-Pituitary-Thyroid axis: thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) respond primarily to circulating serum T₄, converted in the hypothalamus and pituitary to T₃ by the 5′-deiodinase type 2 (D2). The monocarboxylate transporter 8 (MCT8) is required for T₃ transport into the pituitary and hypothalamus. 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. Thyroid hormone receptor signaling is required for the normal development of PBN neurons linking thyroid hormone to cardiac and temperature regulation. B, paraventricular nucleus of the hypothlamus (VPN): leptin, produced in peripheral fat tissue, provides feedback at the VPN, stimulates signal transducer and activator of transcription (STAT)3 phosphorylation (STAT₃-P*), which directly stimulates TRH expression. Leptin also stimulates TRH indirectly in the arcuate nucleus by inhibiting neuropeptide Y and agouti-related protein, stimulating proopiomelanocortin (POMC), and the POMC product α-melanocyte stimulating hormone (α-MSH) stimulates CREB in the TRH neuron (indirect pathway is not shown in Figure 1). C, ventromedial nucleus of the hypothalamus (VMH): hyperthyroidism or T₃ treatment stimulates de novo fatty acid synthesis in the VMH, which inhibits AMPK phosphorylation and increases fatty acid synthase (FAS) activity. Increased hypothalamic lipid synthesis is associated with activation of the sympathetic nervous system (SNS) which stimulates brown adipose tissue (BAT). D, BAT: adrenergic signaling through the β3-adrenergic receptor (AR) stimulates UCP1 gene expression, stimulates D2 activity by deubiquitination, and promotes thermogenesis and weight loss. The metabolic signal from bile acid via the G protein-coupled membrane bile acid receptor (TGR5) has been shown in one model to stimulate D2 activity and local T₃ production, which further stimulates BAT lipolysis, UCP1 expression, and thermogenesis. E, white adipose tissue (WAT): SNS signals via β1- and β2-AR stimulate WAT lipolysis. T₃ stimulates local production of norepinephrine (NE), increasing lipolysis and reducing body fat. F, liver: T₃ is involved in both cholesterol and fatty acid metabolism (see details in Figure 3). HOMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; ACC1, acetyl-CoA carboxylase 1; CYP7a1, cytochrome P-450 7A1; CPT-1α, carnitine palmitoyltransferase 1α; LDL-R, low-density lipoprotein receptor. G, muscle: Forkhead box O3 (FoxO3) induces D2 expression, increases local T₃ in skeletal muscle, and promotes T₃-target gene expression; myoD, myosin heavy chain (MHC) and sarcoplasmic reticulum Ca²⁺-ATPase (SERCA). Local T₃ also determines the relative expression level of MHC and SERCA isoforms. Expression level of these isoforms determines muscle fiber types and initiation of repair. SERCA2a is primarily expressed in slow-twitch fibers and SERCA1 in fast-twitch fibers. T₃ stimulates SERCA, which hydrolyzes ATP and increases energy expenditure. H, pancreas: T₃ and TR are required for normal pancreatic development and function. In rat pancreatic β cells, expression of TR and D2 are activated during normal development. T₃ treatment enhances Mafa (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A) transcription factor gene expression and increases MAFA protein content, the key factor for maturation of β cells to secrete insulin in response to glucose. T₃ stimulates cyclin D1 (CD1) gene expression and protein level and promotes proliferation. Increasing cyclin D1 activates the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway.

FIGURE 2.

Role of corepressors in metabolic regulation. NcoR has three receptor interacting domains (RIDs) located in the COOH terminus. Unliganded TR interacts with RID 2 and 3 and recruits histone deacetylase 3 (HDAC3) to assemble a mediator complex, resulting in basal transcription repression. A: deletion of all three RID (NCoRi) or only RID2–3 (l-NCoRΔID) results in a corepressor that can no longer be recruited to unliganded-TR, although the repression mediator complex can still be assembled since the repression domains are intact. Without NCoR interaction, basal transcription is activated. This activation induces hepatocyte proliferation and T₃- and LXR-target genes activation in liver. B: global expression of the NCoRΔID enhances metabolic actions, such as energy expenditure, and can rescue the RTH phenotype produced by TRβ mutations and increase TH sensitivity. C: the conditional NCoR knockout in specific tissues demonstrates tissue-specific actions of NCoR. After NCoR knockout, basal transcription is activated. Muscle-specific NCoR inactivation enhanced metabolic actions of PPARδ and estrogen-related receptors (ERRs); MEF2, myocyte enhancer factor-2. Adipocyte-specific NCoR−/− enhanced PPARγ actions, inhibited NCoR phosphorylation, leading to constituitive activity, enhanced insulin sensitivity, reduced inflammation, and promoted obesity, consistent with the actions of a PPARγ agonist.

FIGURE 3.

Lipid homeostasis in liver is coordinately regulated by direct actions of T₃ and indirect crosstalk with nutrient-activated nuclear receptors. HMG-CoA reductase, a rate-limiting enzyme in cholesterol synthesis, and sterol response element binding protein (SREBP2) are stimulated by T₃. HMG-CoA reductase is subject to feedback inhibition by cholesterol. The SREBP2 and LXR pathways respond to changes in cellular sterols. When cholesterol levels are low, SREBP2 is activated by LXR-mediated maturation by site 1 and site 2 proteases (S1P and S2P), then transported to the nucleus for activation of its target gene, HMG-CoA reductase. When cellular cholesterol is high, LXR inhibits S1P and S2P resulting in inactive SREBP2, which triggers sterol concentration-dependent HMGCR degradation. This then reduces cholesterol synthesis. CYP7a1 is a rate-limiting enzyme in bile acid synthesis. TR directly stimulates CYP7a1 gene expression in human liver. In mouse, both TR and LXR regulate CYP7a1 expression. Hepatocyte nuclear factor 4 (HNF4) also plays an important role in CYP7a1 gene expression. PPARγ reduces CYP7a1 gene expression by inhibiting HNF4 gene expression. Both TR and LXR play a role in fatty acid synthesis by regulating the expression of acetyl CoA carboxylase (ACC1), fatty acid synthase (FAS), carbohydrate response element binding protein (ChREBP), and SREBP1c. This regulation is mediated by similar DR4 response elements in these gene promoters. Fatty acid β-oxidation is controlled by the rate-limiting enzyme CPT-1α, which transports long-chain fatty acid into the mitochondria for oxidation. A functional TRE and PPRE are located in close proximity (50 bp apart) in the CPT-1α promoter. The mechanism of crosstalk between PPARα and TRα on the CTP-1α promoter has been previously characterized (151). Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the key step initiating gluconeogenesis and is regulated by hormones at the transcriptional level, including T₃. In liver, PPARα ligand inhibits PEPCK mRNA expression. In adipocytes, PPARγ induces PEPCK expression to promote fat storage (not shown in figure). In the presence of glyceraldehyde-3-phosphate (G-3P), triglyceride is synthesized and transported to adipocytes. When energy is needed, there is central activation of the sympathetic nervous system and release of catecholamines, which acts on adipocytes to hydrolyze TG. T₃ increases β-AR expression in adipocytes, which promotes catecholamine-induces lipolysis.