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Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease.

Original publication

DOI

10.1002/path.3984

Type

Journal article

Journal

J Pathol

Publication Date

06/2012

Volume

227

Pages

209 - 222

Keywords

AMP-Activated Protein Kinases, Agouti-Related Protein, Animals, Disease Models, Animal, Eating, Feeding Behavior, Hyperphagia, Hyperthyroidism, Hypothalamus, Male, Neural Pathways, Neuropeptide Y, Phosphorylation, Pro-Opiomelanocortin, Protein Kinase Inhibitors, RNA, Messenger, Rats, Rats, Sprague-Dawley, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Thyroid Hormone Receptors alpha, Time Factors, Triiodothyronine, Weight Loss