Wang Cuizhe, Chu Xiaolong, Deng Yuchun, Wang Jingzhou, Qiu Tongtong, Zhu Jiaojiao, Yang Xin, Pan Chongge, Xiong Jianyu, Xie Jianxin, Chang Yongsheng, Zhang Jun
Medical College of Shihezi University, Bei-Er-Lu, Shihezi, 832000, Xinjiang, China.
Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 300000, China.
Nutr Metab (Lond). 2021 Nov 21;18(1):100. doi: 10.1186/s12986-021-00628-2.
Obesity-induced elevated serum free fatty acids (FFAs) levels result in the occurrence of type 2 diabetes mellitus (T2DM). However, the molecular mechanism remains largely enigmatic. This study was to explore the effect and mechanism of KLF15 on FFAs-induced abnormal glucose metabolism.
Levels of TG, TC, HDL-C, LDL-C, and glucose were measured by different assay kits. qRT-PCR and Western Blot were used to detect the levels of GPR120, GPR40, phosphorylation of p38 MAPK, KLF15, and downstream factors.
KLF15 was decreased in visceral adipose tissue of obesity subjects and high-fat diet (HFD) mice. In HFD mice, GPR120 antagonist significantly promoted KLF15 protein expression level and phosphorylation of p38 MAPK, meanwhile reduced the blood glucose levels. While, blocking GPR40 inhibited the KLF15 expression. In 3T3-L1 adipocytes, 1500 μM PA inhibited KLF15 through a GPR120/P-p38 MAPK signal pathway, and 750 μM OA inhibited KLF15 mainly through GPR120 while not dependent on P-p38 MAPK, ultimately resulting in abnormal glucose metabolism. Unfortunately, GPR40 didn't contribute to PA or OA-induced KLF15 reduction.
Both PA and OA inhibit KLF15 expression through GPR120, leading to abnormal glucose metabolism in adipocytes. Notably, the inhibition of KLF15 expression by PA depends on phosphorylation of p38 MAPK.
肥胖导致血清游离脂肪酸（FFAs）水平升高，进而引发2型糖尿病（T2DM）。然而，其分子机制仍 largely 不明。本研究旨在探讨KLF15对FFAs诱导的异常糖代谢的影响及机制。
使用不同检测试剂盒测量甘油三酯（TG）、总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）和葡萄糖水平。采用qRT-PCR和蛋白质免疫印迹法检测GPR120、GPR40、p38丝裂原活化蛋白激酶（p38 MAPK）的磷酸化水平、KLF15及下游因子的水平。
肥胖受试者和高脂饮食（HFD）小鼠的内脏脂肪组织中KLF15水平降低。在HFD小鼠中，GPR120拮抗剂显著促进KLF15蛋白表达水平和p38 MAPK的磷酸化，同时降低血糖水平。而阻断GPR40则抑制KLF15表达。在3T3-L1脂肪细胞中，1500 μM 棕榈酸（PA）通过GPR120/P-p38 MAPK信号通路抑制KLF15，750 μM 油酸（OA）主要通过GPR120抑制KLF15，且不依赖于P-p38 MAPK，最终导致异常糖代谢。遗憾的是，GPR40对PA或OA诱导的KLF15降低无作用。
PA和OA均通过GPR120抑制KLF15表达，导致脂肪细胞异常糖代谢。值得注意的是，PA对KLF15表达的抑制依赖于p38 MAPK的磷酸化。
