title: Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism.
abstract: 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.
authors.affiliation: Department of Physiology, School of Medicine-CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela (A Coruña) 15782, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Varela
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez-Sánchez
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.forename: María J
authors.initials: MJ
authors.lastname: Vázquez
authors.forename: Juan
authors.initials: J
authors.lastname: Roa
authors.forename: Marina
authors.initials: M
authors.lastname: Gándara
authors.forename: Erik
authors.initials: E
authors.lastname: Schoenmakers
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.forename: Miguel
authors.initials: M
authors.lastname: López
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D054369:Agouti-Related Protein / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D006963:Hyperphagia / Q000201:enzymology / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D006980:Hyperthyroidism / Q000139:chemically induced / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology; D009478:Neuropeptide Y / Q000235:genetics; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D013997:Time Factors; D014284:Triiodothyronine; D015431:Weight Loss
chemical_list: C515197:AGRP protein, rat; D054369:Agouti-Related Protein; D009478:Neuropeptide Y; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D037021:Thyroid Hormone Receptors alpha; D014284:Triiodothyronine; D011333:Pro-Opiomelanocortin; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus