Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Am J Physiol Endocrinol Metab. 2023 May 1;324(5):E449-E460. doi: 10.1152/ajpendo.00329.2022. Epub 2023 Apr 19.
G protein-coupled receptor (GPR) 120 is expressed in enteroendocrine cells secreting glucagon-like peptide-1 (GLP-1), glucose-dependent 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 () mice. In comparison with floxed GPR120 (WT) mice, 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, 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 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 mice. These findings suggest that inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-LCT diet feeding. We generated novel intestine-specific GPR120-knockout () mice and investigated the metabolic effect of GPR120 in the intestine. mice exhibited a reduction of GIP secretion and CCK action after a single administration of LCT. Under a high-LCT diet, 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.
G 蛋白偶联受体 (GPR) 120 表达于分泌胰高血糖素样肽-1 (GLP-1)、葡萄糖依赖性胰岛素释放多肽/胃抑制多肽 (GIP) 和胆囊收缩素 (CCK) 的肠内分泌细胞中。虽然已经报道脂肪组织和巨噬细胞中的 GPR120 信号转导可以改善高脂肪长链甘油三酯 (LCT) 饮食引起的肥胖和胰岛素抵抗，但肠道中 GPR120 的具体作用尚不清楚。为了阐明 GPR120 在肠道中的代谢作用，我们构建了肠道特异性 GPR120 敲除 () 小鼠。与 floxed GPR120 (WT) 小鼠相比，LCT 单次给药后， 小鼠的 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。在高脂肪 LCT 饮食下， 小鼠的体重减轻轻微，胰岛素抵抗和脂肪肝得到显著改善。此外，小鼠的肝脏和白色脂肪组织 (WAT) 中 Akt 磷酸化增加，抑制胰岛素信号的细胞因子信号转导抑制因子 3 (SOCS) 3 的基因表达减少。此外，WAT 中的炎性细胞因子基因表达和肝脏中的脂肪生成分子在 小鼠中减少。这些发现表明，抑制肠道中的 GPR120 信号转导可改善高脂肪 LCT 饮食喂养下的胰岛素抵抗和脂肪肝。我们构建了新型肠道特异性 GPR120 敲除 () 小鼠，并研究了 GPR120 在肠道中的代谢作用。LCT 单次给药后， 小鼠的 GIP 分泌和 CCK 作用减少。在高脂肪 LCT 饮食下， 小鼠的肥胖程度轻微改善，胰岛素抵抗和肝脂肪变性显著改善。我们的结果表明，肠道 GPR120 对胰岛素抵抗和肝脂肪变性有重要作用。
