Inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-fat diet feeding
Inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-fat diet feeding
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DOI：
10.1152/ajpendo.00329.2022
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发表时间：
2023-05-01
影响因子：
5.1
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
--
作者：
Yasuda, Takuma;Harada, Norio;Inagaki, Nobuya
G 蛋白偶联受体 (GPR) 120 在分泌胰高血糖素样肽-1 (GLP-1)、葡萄糖依赖性促胰岛素多肽/胃抑制多肽 (GIP) 和胆囊收缩素 (CCK) 的肠内分泌细胞中表达。尽管据报道，脂肪组织和巨噬细胞中的 GPR120 信号传导可改善高长链甘油三酯 (LCT) 饮食中的肥胖和胰岛素抵抗，但 GPR120 的肠道特异性作用尚不清楚。为了阐明 GPR120 在肠道中的代谢作用，我们培育了肠道特异性 GPR120 敲除 (GPR120int-/-) 小鼠。与floxed GPR120 (WT)小鼠相比，GPR120int-/-小鼠在单次施用LCT后表现出GIP分泌和CCK作用减少，而胰岛素、GLP-1或肽YY (PYY)分泌没有变化。在高LCT饮食下，GPR120int-/-小鼠体重轻微减轻，胰岛素抵抗和脂肪肝显着改善。此外，GPR120int-/-小鼠的肝脏和白色脂肪组织（WAT）表现出Akt磷酸化增加和细胞因子信号传导抑制因子（SOCS）3（抑制胰岛素信号传导）的基因表达减少。此外，GPR120int-/-小鼠中WAT中炎症细胞因子和肝脏中脂肪生成分子的基因表达降低。这些发现表明，在高 LCT 饮食喂养下，抑制肠道 GPR120 信号传导可改善胰岛素抵抗和脂肪肝。新的和值得注意的 我们培育了新型肠道特异性 GPR120 敲除 (GPR120int-/-) 小鼠，并研究了 GPR120 在肠道中的代谢作用。单次给予 LCT 后，GPR120int-/- 小鼠表现出 GIP 分泌和 CCK 作用减少。在高LCT饮食下，GPR120int-/-小鼠的肥胖表现出轻微改善，胰岛素抵抗和肝脂肪变性也得到显着改善。我们的结果表明肠道 GPR120 对胰岛素抵抗和肝脂肪变性具有重要作用。
G protein-coupled receptor (GPR) 120 is expressed in enteroendocrine cells secreting glucagon-like peptide-1 (GLP-1), glucosedependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP), and cholecystokinin (CCK). Although GPR120 signaling in adipose tissue and macrophages has been reported to ameliorate obesity and insulin resistance in a high long-chain triglyceride (LCT) diet, intestine-specific roles of GPR120 are unclear. To clarify the metabolic effect of GPR120 in the intestine, we generated intestine-specific GPR120-knockout (GPR120int-/-) mice. In comparison with floxed GPR120 (WT) mice, GPR120int-/- mice exhibited reduced GIP secretion and CCK action without change of insulin, GLP-1, or peptide YY (PYY) secretion after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed a mild reduction of body weight and substantial amelioration of insulin resistance and fatty liver. Moreover, liver and white adipose tissue (WAT) of GPR120int-/-mice exhibited increased Akt phosphorylation and reduced gene expression of suppressor of cytokine signaling (SOCS) 3, which inhibits insulin signaling. In addition, gene expression of inflammatory cytokines in WAT and lipogenic molecules in liver were reduced in GPR120int-/- mice. These findings suggest that inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-LCT diet feeding. NEW & NOTEWORTHY We generated novel intestine-specific GPR120-knockout (GPR120int-/-) mice and investigated the metabolic effect of GPR120 in the intestine. GPR120int-/- mice exhibited a reduction of GIP secretion and CCK action after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed mild improvement in obesity and marked amelioration of insulin resistance and hepatic steatosis. Our results indicate an important role of intestinal GPR120 on insulin resistance and hepatic steatosis.