Duodenal GLP-1 signaling regulates hepatic glucose production through a PKC-δ-dependent neurocircuitry

Yang, Gangyi; Wang, Jinzhi; Wu, Shaobo; Yuan, Ling; Zhao, Xiaodong; Liu, Chaohong; Xie, Jing; Jia, Yanjun; Lai, Yerui; Zhao, Allan Z.; Boden, Guenther

doi:10.1038/cddis.2017.28

Cited by 29 publications

(33 citation statements)

References 35 publications

(49 reference statements)

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“…The existence of gut–liver communication has been well‐studied in terms of regulating hepatic glucose metabolism either through the vagal–vagal reflex or endocrine hormones . Intestinal mucosa is able to sense luminal nutrients such as lipids and glucose, and alter hepatic gluconeogenesis and glycogenolysis, leading to change in net hepatic glucose output through neuronal network . Intestinal hormones, like cholecystokinin from I cells and glucagon‐like peptide 1 (GLP1) from L cells, are also well‐known for their regulatory effects on glucose metabolism as well .…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

Yin

et al. 2018

Hepatology

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“…For Rac1 activation, the MPHs from WT and DOCK5 À/À mice were treated with SEW2871 (15 nM, Cayman Chemical) for 4 days. Protein expression was analyzed by a Western blot, as indicated previously [50]. Protein expression was analyzed by a Western blot, as indicated previously [50].…”

Section: Measurement Of Rac1 Activationmentioning

confidence: 99%

“…Cell lysates were collected and added to 15 lg PAK-PBD beads [48,49]. Protein expression was analyzed by a Western blot, as indicated previously [50].…”

Section: Measurement Of Rac1 Activationmentioning

confidence: 99%

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DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

et al. 2019

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The dedicator of cytokinesis 5 (DOCK5) is associated with obesity. However, the mechanism by which DOCK5 contributes to obesity remains completely unknown. Here, we show that hepatic DOCK5 expression significantly decreases at a state of insulin resistance (IR). Deletion of DOCK5 in mice reduces energy expenditure, promotes obesity, augments IR, dysregulates glucose metabolism, and activates the mTOR (Raptor)/S6K1 pathway under a high-fat diet (HFD). The overexpression of DOCK5 in hepatocytes inhibits gluconeogenic gene expression and increases the level of insulin receptor (InsR) and Akt phosphorylation. DOCK5 overexpression also inhibits mTOR/S6K1 phosphorylation and decreases the level of raptor protein expression. The opposite effects were observed in DOCK5-deficient hepatocytes. Importantly, in liver-specific Raptor knockout mice and associated hepatocytes, the effects of an adeno-associated virus (AAV8)-or adenovirus-mediated DOCK5 knockdown on glucose metabolism and insulin signaling are largely eliminated. Additionally, DOCK5-Raptor interaction is indispensable for the DOCK5-mediated regulation of hepatic glucose production (HGP). Therefore, DOCK5 acts as a regulator of Raptor to control hepatic insulin activity and glucose homeostasis.

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“…The suppression of plasma glucagon levels by JTP‐109192 treatment under normoglycemic conditions (data not shown) may provide one explanation. It is also reported that the increase of GLP‐1 suppresses the expression of hepatic genes such as phosphoenolpyruvate carboxykinase or glucose 6‐phosphatase involved in glucose production …”

Section: Discussionmentioning

confidence: 99%

Chronic treatment of JTP‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats

Tadaki

Sasase

Fukuda

et al. 2019

Clin Exp Pharma Physio

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G‐protein coupled receptor 119 (GPR119) expression in pancreatic β‐cells and intestinal L cells is a potential therapeutic target for treating type 2 diabetes. A natural GPR119 agonist oleoylethanolamide is well known to enhance a glucose‐stimulated insulin secretion (GSIS) and glucagon‐like peptide‐1 (GLP‐1) secretion by elevating intracellular cAMP levels. In the present study, a glucose lowering effect of the GPR119 agonist, JTP‐109192 leading to improvement of insulin sensitivity was examined in Zucker Fatty (ZF) rats. We investigated the in vitro effects of JTP‐109192 on GSIS in the rat pancreatic β‐cell line (INS1E) cells and on GLP‐1 secretion in the murine enteroendocrine cell line (GLUTag) cells. We also investigated the effect of JTP‐109192 on GSIS in Sprague‐Dawley (SD) rats with single administration and its effect on glucose metabolism in ZF rats with repeated administration once daily for about 6 weeks. After repeated administration, the hyperinsulinaemic euglycaemic glucose clamp test was performed to evaluate insulin sensitivity. JTP‐109192 increased intracellular cAMP levels (EC50 value: 3.6 nmol/L) and enhanced GSIS in the INS1E cells and GLP‐1 secretion in GLUTag cells. In SD rats, a single administration of JTP‐109192 enhanced GSIS at high blood glucose levels. The repeated administrations in ZF rats improved glucose metabolism without lack of drug efficacy (tachyphylaxis) and increased glucose infusion rates due to improvement of insulin sensitivity.

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Duodenal GLP-1 signaling regulates hepatic glucose production through a PKC-δ-dependent neurocircuitry

Cited by 29 publications

References 35 publications

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

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

DOCK5 regulates energy balance and hepatic insulin sensitivity by targeting mTORC1 signaling

Chronic treatment of JTP‐109192, a novel G‐protein coupled receptor 119 agonist, improves metabolic abnormalities in Zucker Fatty rats

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