mTOR signaling in X/A-like cells contributes to lipid homeostasis in mice.

BACKGROUND

Gastric mechanistic target of rapamycin (mTOR) signaling is inversely associated with the expression and secretion of ghrelin, a 28-aa peptide hormone produced by gastric X/A-like cells. Ghrelin contributes to obesity and hepatic steatosis. We sought to control global lipid metabolism through manipulating gastric mTOR signaling in X/A-like cells METHODS: We established a ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of the ghrelin-promoter. mTORflox/flox and TSC1flox/flox mice were separately bred with ghrl-cre mice to generate mTOR-ghrl-cre (mG) or TSC1-ghrl-cre (TG) mice, within which mTOR signaling was suppressed or activated respectively. Lipid metabolism in liver and adipose depots was analyzed RESULTS: Under the control of the ghrelin-promoter, cre enzyme is exclusively expressed in stomach X/A-like cells in adult animals. Knockout of mTOR in X/A-like cells increased circulating acyl-ghrelin and promoted hepatic lipogenesis with effects on adipose depots. Activation of mTOR signaling by deletion of its upstream inhibitor, tuberous sclerosis 1 (TSC1), decreased ghrelin expression and secretion, altering lipid metabolism as evidenced by resistance to high fat diet-induced obesity and hepatic steatosis. Both ghrelin administration and rapamycin, an inhibitor of mTOR, altered the phenotypes of TG mice CONCLUSION: Gastric mTOR signaling in X/A-like cells contributes to organism lipid homeostasis by regulating hepatic and adipose lipid metabolism. Gastric mTOR signaling may provide an alternative strategy for intervention in lipid disorders. This article is protected by copyright. All rights reserved.