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Endogenous Lipid-GPR120 Signaling Modulates Pancreatic Islet Homeostasis to Different Extents

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posted on 26.04.2022, 21:29 authored by Ya-Qin Du, Xue-Ying Sha, Jie Cheng, Jin Wang, Jing-Yu Lin, Wen-Tao An, Wei Pan, Li-Jun Zhang, Xiao-Na Tao, YunFei Xu, Ying-Li Jia, Zhao Yang, Peng Xiao, Ming Liu, Jin-Peng Sun, Xiao Yu

Long-chain fatty acids (LCFAs) not only are energy sources but also serve as signaling molecules. GPR120, an LCFA receptor, plays key roles in maintaining metabolic homeostasis. However, whether endogenous ligand-GPR120 circuits exist and how such circuits function in pancreatic islets are unclear. Here, we found that endogenous GPR120 activity in pancreatic δ cells modulated islet functions. At least two unsaturated LCFAs, oleic acid (OA) and linoleic acid (LA), were identified as GPR120 agonists within pancreatic islets. These two LCFAs promoted insulin secretion by inhibiting somatostatin secretion, and showed bias activation of GPR120 in a model system. Compared to OA, LA exerted higher potency in promoting insulin secretion, which is dependent on β-arrestin2 function. Moreover, GPR120 signaling was impaired in the diabetic db/db model, and replenishing OA and LA improved islet function in both the db/db- and STZ-treated diabetic models. Consistently, the administration of LA improved glucose metabolism in db/db mice. Collectively, our results reveal that endogenous LCFA-GPR120 circuits exist and modulate homeostasis in pancreatic islets. The contributions of phenotype differences caused by different LCFA-GPR120 circuits within islets highlight the roles of fine-tuned ligand–receptor signaling networks in maintaining islet homeostasis.

Funding

We acknowledge support from the National Natural Science Foundation of China Grant (92057121 to X.Y., 32130055 to J.-P.S., 31701230 to Z.Y.), the National Science Fund for Excellent Young Scholars Grant (81822008 to X.Y.), the National Key Basic Research Program of China Grant (2019YFA0904200 to J.-P.S., 2018YFC1003600 to X.Y. and J.-P.S.), the Major Fundamental Research Program of Natural Science Foundation of Shandong Province, China (ZR2021ZD18 to X.Y., ZR2020ZD39 to J.-P.S.), the National Science Fund for Distinguished Young Scholars Grant (81773704 to J.-P.S.), Innovative Research Team in University Grant (IRT_17R68 to X.Y.), the Key Research Project of the Natural Science Foundation of Beijing, China (Z20J00124 to J.-P.S.).

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