Ghrelin-induced food intake and adiposity depend on central mTORC1/S6K1 signaling

• Published in: Molecular and cellular endocrinology Vol. 381; no. 1-2; pp. 280 - 290
• Main Authors: Stevanovic, Darko, Trajkovic, Vladimir, Müller-Lühlhoff, Sabrina, Brandt, Elisabeth, Abplanalp, William, Bumke-Vogt, Christiane, Liehl, Beate, Wiedmer, Petra, Janjetovic, Kristina, Starcevic, Vesna, Pfeiffer, Andreas F.H., Al-Hasani, Hadi, Tschöp, Matthias H., Castañeda, Tamara R.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 05-12-2013
• Subjects: Adipose Tissue, Brown - physiology; adiposity; Adiposity - physiology; Animals; Body weight; Cell Line; Central nervous system; Energy Intake; Food intake; Ghrelin; Ghrelin - physiology; Hypothalamus; Inhibitors; Insulin; Insulin - blood; insulin secretion; Ion Channels - metabolism; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Mitochondrial Proteins - metabolism; mTORC1/S6K; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - metabolism; overeating; Pathways; Phosphorylation; Rapamycin; Rats; Rats, Wistar; Ribosomal Protein S6 Kinases - metabolism; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Uncoupling Protein 1; PBS; mTORC1/S6K; DMSO; Body weight; PKA; Central nervous system; S6K; Insulin; CAMKK2; Ghrelin; Food intake; FBS; NPY; AMPK; GHS-R1a; AgRP; ICV; mTORC1; growth hormone secretagogue receptor type 1a; neuropeptide Y; agouti-related protein; phosphate-buffered saline; AMP-activated protein kinase; dimethyl sulfoxide; intracerebroventricular; S6 kinases; protein kinase A; mammalian target of rapamycin complex 1; fetal bovine serum; calmodulin-dependent kinase kinase 2
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2013.08.009

•Ghrelin’s metabolic effects are mediated by the mTORC1/S6K1 pathway.•Ghrelin control of plasma insulin is mediated through the mTORC1/S6K1 pathway.•These effects occur at the level of the central nervous system.
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.