Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin

• Published in: PloS one 2012-10, Vol.7 (10), p.e46923-e46923
• Main Authors: Martins, Luís, Fernández-Mallo, Diana, Novelle, Marta G, Vázquez, María J, Tena-Sempere, Manuel, Nogueiras, Rubén, López, Miguel, Diéguez, Carlos
• Format: Article
• Language: English
• Subjects: Agouti-related protein; Agouti-Related Protein - metabolism; AMP; AMP-activated protein kinase; Animals; Appetite Stimulants - administration & dosage; Appetite Stimulants - pharmacology; Arcuate nucleus; Arcuate Nucleus of Hypothalamus - cytology; Arcuate Nucleus of Hypothalamus - drug effects; Arcuate Nucleus of Hypothalamus - metabolism; Arcuate Nucleus of Hypothalamus - physiology; Biology; Brain; Chronic illnesses; Diabetes; DNA binding proteins; Eating - drug effects; Endocrinology; Energy; Experiments; Fatty acids; Feeding Behavior - drug effects; Feeding Behavior - physiology; Forkhead protein; FOXO1 protein; Gene expression; Ghrelin; Ghrelin - administration & dosage; Ghrelin - pharmacology; Hypothalamus; Hypothalamus - cytology; Hypothalamus - drug effects; Hypothalamus - metabolism; Hypothalamus - physiology; Kinases; Male; Medicine; Metabolic pathways; Metabolism; Metabolites; Modulation; Neuropeptide Y; Neuropeptide Y - metabolism; Neuropeptides; p53 Protein; Peptides; Physiology; Protein binding; Protein kinases; Proteins; Rapamycin; Rats; Rats, Sprague-Dawley; RNA; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; SIRT1 protein; Stomach; Thyroid gland; Time Factors; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription factors; Transcription Factors - metabolism; Tumor proteins
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0046923

Current evidence suggests that ghrelin, a stomach derived peptide, exerts its orexigenic action through specific modulation of Sirtuin1 (SIRT1)/p53 and AMP-activated protein kinase (AMPK) pathways, which ultimately increase the expression of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARC). However, there is a paucity of data about the possible action of ghrelin on alternative metabolic pathways at this level. Here, we demonstrate that ghrelin elicits a marked upregulation of the hypothalamic mammalian target of rapamycin (mTOR) signaling pathway. Of note, central inhibition of mTOR signaling with rapamycin decreased ghrelin's orexigenic action and normalized the mRNA expression of AgRP and NPY, as well as their key downstream transcription factors, namely cAMP response-element binding protein (pCREB) and forkhead box O1 (FoxO1, total and phosphorylated). Taken together, these data indicate that, in addition to previous reported mechanisms, ghrelin also promotes feeding through modulation of hypothalamic mTOR pathway.