A novel GPR120-selective agonist promotes insulin secretion and improves chronic inflammation
A novel GPR120-selective agonist promotes insulin secretion and improves chronic inflammation
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一种新型 GPR120 选择性激动剂促进胰岛素分泌并改善慢性炎症
DOI：
10.1016/j.lfs.2021.119029
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
He-Yao Wang
中科院分区：
文献类型：
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作者：
Liu Yang;Xian-Tao Lei;Qi Huang;Ting Wang;Hong-Bin Sun;He-Yao Wang
本研究旨在揭示一种有效的、选择性的GPR120激动剂LXT34及其抗糖尿病作用。主要方法采用钙动员法测定LXT34对过表达GPR120或gpr40的中国仓鼠卵巢（CHO）细胞的拮抗效力和选择性。采用酶联免疫吸附试验（ELISA）分别测定人结肠上皮细胞系NCI-H716和小鼠胰岛素瘤细胞系MIN6中胰高血糖素样肽-1 （GLP-1）的释放和葡萄糖刺激胰岛素分泌（GSIS）。在脂多糖（LPS）诱导的小鼠巨噬细胞RAW264.7中测定其抗炎作用。采用口服糖耐量试验（OGTT）和胰岛素耐量试验（ITT）评估LXT34对小鼠的抗糖尿病作用，并采用组织形态学、免疫印迹和基因表达分析研究LXT34对小鼠肝脏和脂肪组织慢性炎症的影响。slxt34是一种有效的GPR120激动剂，对人和小鼠GPR40的活性可以忽略不计。LXT34可增强巨噬细胞GSIS，抑制lps诱导的炎症。LXT34不仅能显著改善糖耐量和胰岛素抵抗，还能显著降低小鼠肝脏和脂肪组织巨噬细胞浸润、促炎细胞因子表达和JNK磷酸化。elxt34是一种新型有效的gpr120选择性激动剂，对改善肥胖相关2型糖尿病的葡萄糖稳态有有益作用。
AimsThe present study aimed to disclose a potent and selective GPR120 agonist LXT34 and its anti-diabetic effects.Main methodsCalcium mobilization assay was used to measure the agonistic potency and selectivity of LXT34 in GPR120 or GPR40-overexpression Chinese hamster ovary (CHO) cells. Glucagon-like peptide-1 (GLP-1) release and glucose-stimulated insulin secretion (GSIS) were evaluated in human colonic epithelial cell line NCI-H716 and mouse insulinoma cell line MIN6 by enzyme-linked immunosorbent assay (ELISA), respectively. The anti-inflammatory effect was determined in lipopolysaccharide (LPS)-induced murine macrophage cell line RAW264.7. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed to assess the anti-diabetic effects of LXT34 indb/dbmice, and chronic inflammation in liver and adipose tissues were investigated using histomorphology, immunoblot and gene expression analysis.Key findingsLXT34 was a potent GPR120 agonist with negligible activity toward human and mouse GPR40. LXT34 could potentiate GSIS and suppress LPS-induced inflammation in macrophages. LXT34 not only markedly improved glucose tolerance and insulin resistance, but also distinctly reduced macrophages infiltration, pro-inflammatory cytokines expression and JNK phosphorylation of both liver and adipose tissues indb/dbmice.SignificanceLXT34, a novel and potent GPR120-selective agonist, showed beneficial effects on improving glucose homeostasis in obesity-related type 2 diabetes.