title: Ghrelin-induced food intake and adiposity depend on central mTORC1/S6K1 signaling.
abstract: Signaling through the mammalian target of rapamycin complex 1 (mTORC1) and its effectors the S6-kinases (S6K) in the hypothalamus is thought to be involved in nutrient sensing and control of food intake. Given the anatomical proximity of this pathway to circuits for the hormone ghrelin, we investigated the potential role of the mTORC1/S6K pathway in mediating the metabolic effects of ghrelin. We found that ghrelin promoted phosphorylation of S6K1 in the mouse hypothalamic cell line N-41 and in the rat hypothalamus after intracerebroventricular administration. Rapamycin, an inhibitor of mTORC1, suppressed ghrelin-induced phosphorylation of hypothalamic S6K1 and increased food intake and insulin in rats. Chronic peripheral administration of ghrelin induced a significant increase in body weight, fat mass and food efficiency in wild-type and S6K2-knockout but not in S6K1-knockout mice. We therefore propose that ghrelin-induced hyperphagia, adiposity and insulin secretion are controlled by a central nervous system involving the mTORC1/S6K1 pathway.
authors.affiliation: Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam Rehbrücke, Germany; Institute of Physiology, School of Medicine, University of Belgrade, Serbia.
authors.forename: Darko
authors.initials: D
authors.lastname: Stevanovic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trajkovic
authors.forename: Sabrina
authors.initials: S
authors.lastname: Müller-Lühlhoff
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brandt
authors.forename: William
authors.initials: W
authors.lastname: Abplanalp
authors.forename: Christiane
authors.initials: C
authors.lastname: Bumke-Vogt
authors.forename: Beate
authors.initials: B
authors.lastname: Liehl
authors.forename: Petra
authors.initials: P
authors.lastname: Wiedmer
authors.forename: Kristina
authors.initials: K
authors.lastname: Janjetovic
authors.forename: Vesna
authors.initials: V
authors.lastname: Starcevic
authors.forename: Andreas F H
authors.initials: AF
authors.lastname: Pfeiffer
authors.forename: Hadi
authors.initials: H
authors.lastname: Al-Hasani
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Tamara R
authors.initials: TR
authors.lastname: Castañeda
mesh_terms: D002001:Adipose Tissue, Brown / Q000502:physiology; D050154:Adiposity / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002149:Energy Intake; D054439:Ghrelin / Q000502:physiology*; D007328:Insulin / Q000097:blood; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071256:Uncoupling Protein 1
chemical_list: D054439:Ghrelin; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D000071256:Uncoupling Protein 1; C546845:mTOR protein, rat; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; C526901:Rps6kb1 protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: AMP-activated protein kinase; AMPK; AgRP; Body weight; CAMKK2; Central nervous system; DMSO; FBS; Food intake; GHS-R1a; Ghrelin; ICV; Insulin; NPY; PBS; PKA; S6 kinases; S6K; agouti-related protein; calmodulin-dependent kinase kinase 2; dimethyl sulfoxide; fetal bovine serum; growth hormone secretagogue receptor type 1a; intracerebroventricular; mTORC1; mTORC1/S6K; mammalian target of rapamycin complex 1; neuropeptide Y; phosphate-buffered saline; protein kinase A