Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance

Abstract

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here, we demonstrate that either whole body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly inhibition of thyroid hormone receptors (TRs) in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation as genetic ablation of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid-hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is an important regulator of energy homeostasis.

Thyroid hormone action in metabolic regulation

“…It is not clear whether non-genomic effect of TR also plays a role in sustaining energy metabolism. A recent study showed that AMPK activity is regulated by thyroid hormone in CNS (López et al, 2010); however, the authors did not point out whether such regulation belongs to non-genomic action of TR or not. In addition to AMPK signaling, MAPK and PI3K/AKT signaling have been shown to be regulated by thyroid hormone.…”

Brown and beige fat: development, function and therapeutic potential

“…For example, thyroid hormone directly induces the expression of thermogenic genes in brown adipocytes through the actions of thyroid receptors and also functions centrally to activate BAT [142][143][144] . Along similar lines, the neurotransmitter orexin augments BAT function by regulating sympathetic outflow and through directly promoting brown fat precursor differentiation 145,146 (Fig.…”

Adenosine Monophosphate-Activated Protein Kinase: A Central Regulator of Metabolism with Roles in Diabetes, Cancer, and Viral Infection

“…Both leptin and the thyroid hormone T3 were reported to inhibit or down-regulate AMPK in the hypothalamus, and this was associated with increased activity of the sympathetic nervous system. This caused increased fat oxidation in skeletal muscle in response to leptin, a response that had a longer time course than the direct effects of the hormone on muscle , and increased expression of markers of thermogenesis in brown adipose tissue in response to T3 (Lopez et al 2010). These effects help to explain how these hormones increase energy expenditure and/or heat production.…”