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

Xu, Geyang; Li, Yin; An, Wenjiao; Li, Shenduo; Guan, Youfei; Wang, Nanping; Tang, Chaoshu; Wang, Xian; Zhu, Yi; Li, Xiaoying; Mulholland, Michael W.; Zhang, Weizhen

doi:10.1210/en.2009-0372

Cited by 87 publications

(93 citation statements)

References 40 publications

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“…Conversely, activation of gastric mTOR signaling attenuates the expression and secretion of ghrelin. All these data support the concept that gastric mTOR activity is reciprocally linked to the production of ghrelin [5] .…”

Section: Gastric Mtor and Hormone Productionsupporting

confidence: 79%

“…Gastric mTOR activity decreases in 48 h fasted mice relative to fed animals. In contrast, there is a significant increase in gastric phospho-mTOR (Ser2448) and phospho-S6 (Ser235/236) expression in obese mice relative to lean animals [5] . Gastric mTOR signaling is therefore reciprocally related with the short-and long-term changes in nutritional status at the organism level.…”

Section: Co-localization Of Mtor Signaling Molecules In Gastric Neuromentioning

confidence: 83%

“…interaction between peripheral and central fuel sensing mechanisms is a crucial feature of feeding behavior and energy homeostasis [5] . The peripheral fuel sensing mechanism in the gastric mucosa may function to regulate the production of gastric hormones and therefore contribute to the modulation of energy metabolism.…”

Section: Guidelines For Basic Sciencementioning

confidence: 99%

“…A series of studies have identified mTOR as a potential candidate of fuel sensor in the gastric mucosa because of its expression in a distinct group of the gastric endocrine cells, its reciprocal relationship with energy status and its role in the regulation of gastric hormone production [1,5,20] .…”

Section: Gastric Mtor Is a Fuel Sensor Integrating Fuel Supply With Hmentioning

confidence: 99%

“…All these hormones are proposed to modulate the activity of the energy metabolism center within the hypothalamus, ultimately leading to a change in feeding behavior and the control of metabolic homeostasis [2] . While many studies reveal that nutrient sensing molecules within the hypothalamic neurons are critical in the control of energy homeostasis [3] and defects in fuel sensing at the hypothalamic cellular level may lead to energy imbalance at the organism level and to the development of obesity [4] , a recent study suggests that there also exists a fuel sensing mechanism in the gastric mucosa [5] . This finding suggests that the…”

Section: Introductionmentioning

confidence: 99%

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Gastric mammalian target of rapamycin signaling, hormone production and energy metabolism

Li²,

Zhang

2011

WJGP

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The obesity epidemic imposes a significant health burden on human beings. Current understanding of the mechanisms underlying the development of obesity is incomplete and contemporary treatment is often ineffective. Gastrointestinal hormones are important regulators of food intake and energy metabolism. Previous studies indicate that the mammalian target of rapamycin signaling pathway in the gastric mucosa is crucially involved in fuel sensing in the gastrointestinal tract and plays a critical role in the coordination of nutrient availability and ingestive behavior via the production of gastric hormones. As an important component of the brain-gut axis regulating food intake and energy homeostasis, energy sensing in the gastrointestinal tract may provide a novel insight into our understanding of the precise coordination between the organism and cellular energy state.

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Section: Gastric Mtor and Hormone Productionsupporting

confidence: 79%

Section: Co-localization Of Mtor Signaling Molecules In Gastric Neuromentioning

confidence: 83%

Section: Guidelines For Basic Sciencementioning

confidence: 99%

Section: Gastric Mtor Is a Fuel Sensor Integrating Fuel Supply With Hmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gastric mammalian target of rapamycin signaling, hormone production and energy metabolism

Li²,

Zhang

2011

WJGP

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

Yin

et al. 2018

Hepatology

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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 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.

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Ghrelin ameliorates nonalcoholic steatohepatitis induced by chronic low‐grade inflammation via blockade of Kupffer cell M1 polarization

Yin

Wang

et al. 2020

Journal Cellular Physiology

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Whether the stomach influences the progression of nonalcoholic steatohepatitis (NASH) remains largely unknown. Ghrelin, a 28‐amino acid gastric hormone, is critical for the regulation of energy metabolism and inflammation. We investigated whether ghrelin affects the progression of NASH. NASH was induced with lipopolysaccharide (LPS; 240 μg/kg/day) in male C57BL/6J mice with high‐fat diet (HFD). Ghrelin (11 nmol/kg/day) was administrated by a subcutaneous mini‐pump. Liver steatosis, inflammation, and fibrosis were assessed. Kupffer cells and hepatocytes isolated from wild type, GHSR1a−/− or PPARγ+/− mice were cocultured to determine the cellular and molecular mechanism by which ghrelin ameliorates NASH. A low concentration of LPS activates the Kupffer cells, leading to the development of NASH in mice fed HFD. Ghrelin blocked the progression of NASH induced by LPS via GHSR1a‐mediated attenuation of Kupffer cells M1 polarization. GHSR1a was detected in Kupffer cells isolated from wild‐type mice but not in GHSR1a deficient animals. Upon binding with ghrelin, internalization of GHSR1a occurred. Ghrelin reduced levels of tumor necrosis factor‐α and inducible nitricoxide synthase while increasing Arg1 in Kupffer cells treated with LPS. Ghrelin markedly attenuated the upregulation of lipid accumulation induced by the supernatant of Kupffer cells under both basal and LPS‐treated conditions. Deficiency of PPARγ significantly reduced the effect of LPS on the hepatic steatosis in mice and in cultured hepatocytes. Our studies indicate that the stomach may improve the development of NASH via ghrelin. Ghrelin may serve as a marker and therapeutic target for NASH.

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

Cited by 87 publications

References 40 publications

Gastric mammalian target of rapamycin signaling, hormone production and energy metabolism

Gastric mammalian target of rapamycin signaling, hormone production and energy metabolism

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

Ghrelin ameliorates nonalcoholic steatohepatitis induced by chronic low‐grade inflammation via blockade of Kupffer cell M1 polarization

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