| Summary: | 碩士 === 國立陽明大學 === 生理學研究所 === 105 === Metabolic syndrome included obesity, insulin resistance, dyslipidemia, hyperglycemia, and hypertension. Obesity is a risk factor of metabolic syndrome. Previous studies showed that obesity would cause chronic inflammatory response and may contribute insulin resistance. Activation of CCR5 (C-C motif chemokine receptor 5) by RANTES (regulated on activation, normal T cell expressed and secreted) binding can stimulates monocyte, eosinophil, basophil, and T-lymphocyte chemotaxis. Studies demonstrated that CCR5 expression was significantly increased in adipose tissue of obese mice. In addition, CCR5 knockout mice were protected from insulin resistance induced by high-fat diet feeding. But a contradictory result had been reported that loss of CCR5 resulted in glucose intolerance in diet-induced obese mice. These observations suggested the effect of CCR5 activation on insulin sensitivity is controversial. The aim of our study is to investigate the effect of CCR5 activation on insulin-stimulated glucose uptake in C2C12 cell. In the present study, C2C12 cells were treated with RANTES and/or CCR5 inhibitor (Maraviroc) for 24 hours, then insulin signaling and insulin-stimulated glucose uptake were measured by western blotting and NBDG uptake. Besides, the underlying mechanisms were clarified by using inhibitors specific to CCR5 signaling. The results showed that treatment of RANTES decreased insulin-stimulated Akt phosphorylation and NBDG uptake in C2C12 cells. Besides, pretreatment of Maraviroc significantly improved the RANTES-impaired insulin-stimulated Akt phosphorylation and NBDG uptake. Moreover, RANTES increased ser307 phosphorylation of IRS1 and pretreatment of Maraviroc significantly suppressed RANRES-stimulated ser307 phosphorylation of IRS1. In conclusion, activation of CCR5 inhibited the insulin signaling and subsequent glucose uptake in skeletal muscle cells through ERK-dependent pathway.
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