GPR120 protects lipotoxicity-induced pancreatic beta-cell dysfunction through regulation of PDX1 expression and inhibition of islet inflammation.

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 beta cells remains unclear. To explore the potential link between GPR120 and beta-cell function, its agonist DHA and GSK137647AS were used in palmitic acid (PA)-induced pancreatic beats-cell dysfunction, coupled with GPR120 KD in MIN6 cells and GPR120 KO mice to identify the underlying signalling pathways. In vitro and ex vivo treatments of MIN6 cells and islets isolated from WT mice with DH and GSK restored pancreatic PDX1 expression levels and beta-cell function via PA-induced elevation of proinflammatory chemokine and activation of NF-kB, JNK and p38MAPK signalling pathways. On the contrary, these GPR120 agonism-mediated protective effects were abolished in GPR120 KD cells and islets from GPR120 KO mice. Furthermore, GPR120 KO mice displayed glucose intolerance and insulin resistance relative to WT littermate, and beta-cell functional related genes were decreased while inflammation was exacerbated in islets with increased macrophages in pancreas from GPR120 KO mice. DHA and GSK supplementation ameliorated glucose tolerance and insulin sensitivity, as well as improved pdx1 expression and islet inflammation in diet-induced obese WT mice, but not in GPR120 KO mice. These findings indicate that GPR120 activation is protective and against lipotoxicity-indcued pancreatic beta-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.