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Gastric Mammalian Target of Rapamycin Signaling Regulates Ghrelin Production and Food Intake

Department of Physiology and Pathophysiology (G.X., Y.L., W.A., S.L., Y.G., N.W., C.T., X.W., Y.Z., W.Z.), Peking University Health Science Center, Beijing 100083, China; Department of Surgery (M.W.M., W.Z.), University of Michigan Medical Center, Ann Arbor, Michigan 48109; and Shanghai Institute of Endocrinology and Metabolism Research (X.L.), Ruijin Hospital, Shanghai Jiaotong University, Medical School, Shanghai 200025, China

Address all correspondence and requests for reprints to: Weizhen Zhang, Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing 100083, China. E-mail: weizhenzhang{at}bjmu.edu.cn; or Michael W. Mulholland, Department of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0346. E-mail: micham{at}umich.edu.

Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate food intake. Mammalian target of rapamycin (mTOR) is an intracellular fuel sensor critical for cellular energy homeostasis. Here we showed the reciprocal relationship of gastric mTOR signaling and ghrelin during changes in energy status. mTOR activity was down-regulated, whereas gastric preproghrelin and circulating ghrelin were increased by fasting. In db/db mice, gastric mTOR signaling was enhanced, whereas gastric preproghrelin and circulating ghrelin were decreased. Inhibition of the gastric mTOR signaling by rapamycin stimulated the expression of gastric preproghrelin and ghrelin mRNA and increased plasma ghrelin in both wild-type and db/db mice. Activation of the gastric mTOR signaling by L-leucine decreased the expression of gastric preproghrelin and the level of plasma ghrelin. Overexpression of mTOR attenuated ghrelin promoter activity, whereas inhibition of mTOR activity by overexpression of TSC1 or TSC2 increased its activity. Ghrelin receptor antagonist D-Lys-3-GH-releasing peptide-6 abolished the rapamycin-induced increment in food intake despite that plasma ghrelin remained elevated. mTOR is therefore a gastric fuel sensor whose activity is linked to the regulation of energy intake through ghrelin.

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