School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
Clin Sci (Lond). 2019 Jan 11;133(1):101-116. doi: 10.1042/CS20180836. Print 2019 Jan 15.
G-protein coupled receptor 120 (GPR120) has been shown to act as an omega-3 unsaturated fatty acid sensor and is involved in insulin secretion. However, the underlying mechanism in pancreatic β cells remains unclear. To explore the potential link between GPR120 and β-cell function, its agonists docosahexaenoic acid (DHA) and GSK137647A were used in palmitic acid (PA)-induced pancreatic β-cell dysfunction, coupled with GPR120 knockdown (KD) in MIN6 cells and GPR120 knockout (KO) mice to identify the underlying signaling pathways. and treatments of MIN6 cells and islets isolated from wild-type (WT) mice with DHA and GSK137647A restored pancreatic duodenal homeobox-1 (PDX1) expression levels and β-cell function via inhibiting PA-induced elevation of proinflammatory chemokines and activation of nuclear factor κB, c-Jun amino (N)-terminal kinases1/2 and p38MAPK signaling pathways. On the contrary, these GPR120 agonism-mediated protective effects were abolished in GPR120 KD cells and islets isolated from GPR120 KO mice. Furthermore, GPR120 KO mice displayed glucose intolerance and insulin resistance relative to WT littermates, and β-cell functional related genes were decreased while inflammation was exacerbated in islets with increased macrophages in pancreas from GPR120 KO mice. DHA and GSK137647A supplementation ameliorated glucose tolerance and insulin sensitivity, as well as improved expression and islet inflammation in diet-induced obese WT mice, but not in GPR120 KO mice. These findings indicate that GPR120 activation is protective against lipotoxicity-induced pancreatic β-cell dysfunction, via the mediation of PDX1 expression and inhibition of islet inflammation, and that GPR120 activation may serve as a preventative and therapeutic target for obesity and diabetes.
G 蛋白偶联受体 120（GPR120）已被证明作为 ω-3 不饱和脂肪酸传感器发挥作用，并参与胰岛素分泌。然而，其在胰岛β细胞中的潜在机制尚不清楚。为了探讨 GPR120 与β细胞功能之间的潜在联系，在棕榈酸（PA）诱导的胰岛β细胞功能障碍中使用其激动剂二十二碳六烯酸（DHA）和 GSK137647A，并用 MIN6 细胞和 GPR120 敲除（KO）小鼠中的 GPR120 敲低（KD）来鉴定潜在的信号通路。DHA 和 GSK137647A 处理 MIN6 细胞和来自野生型（WT）小鼠的胰岛，可恢复胰岛十二指肠同源盒-1（PDX1）的表达水平和β细胞功能，其机制为抑制 PA 诱导的前炎症趋化因子升高和核因子κB、c-Jun 氨基（N）-末端激酶 1/2 和 p38MAPK 信号通路的激活。相反，在 GPR120 KD 细胞和 GPR120 KO 小鼠的胰岛中，这些 GPR120 激动剂介导的保护作用被消除。此外，与 WT 同窝仔相比，GPR120 KO 小鼠表现出葡萄糖不耐受和胰岛素抵抗，β细胞功能相关基因减少，而胰岛炎症加剧，胰腺中巨噬细胞增加。DHA 和 GSK137647A 的补充改善了肥胖 WT 小鼠的葡萄糖耐量和胰岛素敏感性，以及改善了 表达和胰岛炎症，但在 GPR120 KO 小鼠中则没有。这些发现表明，GPR120 的激活通过 PDX1 表达的介导和胰岛炎症的抑制对脂毒性诱导的胰岛β细胞功能障碍具有保护作用，并且 GPR120 的激活可能成为肥胖和糖尿病的预防和治疗靶点。
