mTOR Signaling in X/A‐Like Cells Contributes to Lipid Homeostasis in Mice

Abstract

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. mTOR and TSC1 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.

Physiological Effect of Ghrelin on Body Systems

“…Fasting increases gastric ghrelin mRNA expression in mice and rats [32,33]. Expression and secretion of ghrelin are inversely associated with the gastric mechanistic target of rapamycin (mTOR) signaling [34]. Knockout of mTOR in X/A-like cells increases circulating acyl ghrelin.…”

mTOR Pathway is Involved in Energy Homeostasis Regulation as a Part of the Gut–Brain Axis

“…Gastric ghrelin production was significantly reduced in this mouse model, which occurs in parallel with reduced food intake. In addition to the effects described on fat content, a decrease in liver fat was also observed in these mice, which was associated in the literature with decreased ghrelin levels [ 70 ]. Consequently, with this lower lipid content, the main hepatic signaling pathways involved in lipogenesis are decreased in the mouse model (srebf1, srebf2, pparγ and pparγ2), and the expression of oxidation related genes is increased.…”

“…The mice model of genetic mTOR activation specifically in X/A cells presents decreased body weight and fat adipose content than its wild type without significant differences in food intake, according to unaffected expression of the main hypothalamic genes regulating appetite (NPY, AGRP and POMC). The leaner phenotype of mice with activated mTOR in X/A cells is probably due to a decrease in the gastric expression and secretion of ghrelin [ 70 ].…”

“…When mTOR activation in the stomach was selectively performed in gastric X/A-like cells, hepatic lipogenesis was suppressed and β-oxidation was stimulated. Furthermore, it was demonstrated that mTOR activity in X/A type cells regulates hepatic lipid metabolism, partially through ghrelin [ 70 ]. This is corroborated by previous studies in which authors observed that ghrelin induces lipogenesis in hepatocytes by mTOR signaling [ 41 ].…”

“…In addition to the effects in the liver, adipose tissue was also affected in the mice with the knockdown of gastric TSC1, as evidenced by the smaller size of adipocytes in parallel with the lower expression of the main genes involved in de novo lipogenesis in adipose tissue and browning (UCP1). Furthermore, these effects are independent of the affected insulin control that these mice showed [ 70 ].…”