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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 via the manipulation of gastric mTOR signaling in X/A-like cells. 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 flox/flox and tuberous sclerosis 1 (TSC1) flox/flox mice were separately bred with ghrl-cre mice to generate mTOR-ghrl-cre or TSC1-ghrl-cre mice, within which mTOR signaling was suppressed or activated, respectively. Lipid metabolism in liver and adipose depots was analyzed. Under the control of the ghrelin-promoter, the Cre enzyme was 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, 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 injection of rapamycin, an inhibitor of mTOR, altered the phenotypes of TSC1-ghrl-cre 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., (© 2018 by the American Association for the Study of Liver Diseases.)

Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.

Although ghrelin has been demonstrated to stimulate energy intake and storage through a central mechanism, its effect on hepatic lipid metabolism remains largely uncharacterized. Ghrelin receptor antagonism or gene deletion significantly decreased obesity-associated hepatic steatosis by suppression of de novo lipogenesis, whereas exogenous ghrelin stimulated lipogenesis, leading to hepatic lipid accumulation in mice. The effects of ghrelin were mediated by direct activation of its receptor on hepatocytes. Cultured hepatocytes responded to ghrelin with increased lipid content and expression of lipogenesis-related genes. Ghrelin increased phosphorylation of S6, the downstream target of mammalian target of rapamycin (mTOR) signaling in cultured hepatocytes, whereas ghrelin receptor antagonism reduced hepatic phosphorylation of S6 in db/db mice. Inhibition of mTOR signaling by rapamycin markedly attenuated ghrelin-induced up-regulation of lipogenesis in hepatocytes, whereas activation of hepatic mTOR signaling by deletion of TSC1 increased hepatic lipogenesis. By interacting with peroxisome proliferator-activated receptor-γ (PPARγ), mTOR mediates the ghrelin-induced up-regulation of lipogenesis in hepatocytes. The stimulatory effect of ghrelin on hepatic lipogenesis was significantly attenuated by PPARγ antagonism in cultured hepatocytes and in PPARγ gene-deficient mice. Our study indicates that ghrelin activates its receptor on hepatocytes to promote lipogenesis via a mechanism involving the mTOR-PPARγ signaling pathway.

Background & Aims: Ghrelin, a gut hormone with pleiotropic effects, may act as a protective signal in parenchymal cells. We investigated the protective effects of ghrelin on hepatocytes after ischaemia/reperfusion (I/R)., Methods: Hepatic injury was assessed by measurement of plasma alanine aminotransferase (ALT) and lactate dehydrogenase (LDH), histological analysis, and TUNEL assay. Effects of exogenous ghrelin and ghrelin receptor gene deletion on I/R induced injury of liver were evaluated., Results: Ischaemia/reperfusion induced a profound injury to hepatocytes. This was accompanied by elevations in plasma ALT and LDH. Pretreatment with ghrelin significantly reduced elevations in plasma ALT and LDH, and attenuated tissue damage induced by hepatic I/R in mice. Hepatic injury induced by I/R was more pronounced in ghrelin receptor gene null mice. Ghrelin administration blocked the up-regulation of AMP-activated protein kinase (AMPK) activity induced by hepatic I/R., Conclusions: This study demonstrates that ghrelin contributes to the cytoprotection during hepatic I/R., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims/hypothesis: Rapamycin impairs glucose tolerance and insulin sensitivity. Our previous study demonstrated that rapamycin significantly increases the production of gastric ghrelin, which is critical in the regulation of glucose metabolism. Here, we investigated whether ghrelin contributes to derangements of glucose metabolism induced by rapamycin., Methods: The effects of rapamycin on glucose metabolism were examined in mice receiving ghrelin receptor antagonist or with Ghsr1a gene knockout. Changes in GLUT4, c-Jun N-terminal kinase (JNK) and phosphorylated ribosomal protein S6 (pS6) were investigated by immunofluorescent staining or western blotting. Related hormones were detected by radioimmunoassay kits., Results: Rapamycin impaired glucose metabolism and insulin sensitivity not only in normal C57BL/6J mice but also in both obese mice induced by a high fat diet and db/db mice. This was accompanied by elevation of plasma acylated ghrelin. Rapamycin significantly increased the levels of plasma acylated ghrelin in normal C57BL/6J mice, high-fat-diet-induced obese mice and db/db mice. Elevation in plasma acylated ghrelin and derangements of glucose metabolism upon administration of rapamycin were significantly correlated. The deterioration in glucose homeostasis induced by rapamycin was blocked by D: -Lys3-GHRP-6, a ghrelin receptor antagonist, or by deletion of the Ghsr1a gene. Ghrelin receptor antagonism and Ghsr1a knockout blocked the upregulation of JNK activity and downregulation of GLUT4 levels and translocation in the gastrocnemius muscle induced by rapamycin., Conclusions/interpretation: The current study demonstrates that ghrelin contributes to derangements of glucose metabolism induced by rapamycin via altering the content and translocation of GLUT4 in muscles.

The mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase, is an intracellular fuel sensor critical for cellular energy homeostasis. Gastrointestinal endocrine cells play a vital role in the regulation of energy balance by secreting hormones that inform the brain about energy supply. Here we showed the localization of mTOR signaling molecules in more than 90% of gastric ghrelin cells and 36±3% of gastrin cells, while no somatostatin-positive cell showed phospho-S6K1 immunoreactivity. Inhibition of mTOR significantly stimulated expression of gastric ghrelin mRNA and protein, and the concentration of plasma ghrelin (2.06±0.34 ng/ml vs. 12.53±3.9 ng/ml, p<0.05), inhibited gastrin synthesis and secretion (75.01±6.71 pg/ml vs. 54.04±3.65 pg/ml, p<0.05), but had no effect on somatostatin production (165.2±25.07 pg/ml vs. 178.9±29.14 pg/ml, p=0.73). Gastric mTOR is a gastric sensor whose activity is linked to the differential regulation of gastric hormone production and release., (Copyright © 2010 Elsevier Inc. All rights reserved.)