| Summary: | 碩士 === 國防醫學院 === 生理學研究所 === 100 === Background:
Obesity has been considered as a chronic low-grade inflammatory disease, which is closely linked with adipose proinflammatory chemokine and cytokine production ,and insulin resistance. In addition, obesity also influence insulin secretion and viability of pancreatic cells.
Purpose:
The aim of this study was undertaken to investigate the role of CCR5 mediated inflammatory pathway in obesity-associated adipose tissue inflammation and glucose tolerance as well as impairment of pancreatic insulin secretion and cell survival in high-fat fed animal model.
Materials and methods:
The male Sprague-Dawley rats weighed 200-220g were fed regular chow or 45% high-fat enriched diet（HFD）for 8 weeks respectively. Then, the rats were further divided into two subgroups co-treated with Maraviroc（30mg/kg/day P.O.）or vehicle for 4 weeks. The body weight and food intake were measured once a week .The oral glucose tolerance test（OGTT）was assessed at the end of study. Adipocyte size and adipokine production in adipocyte-derived conditional medium were examined at the end of study.
The CCR5 gene knockout and wild type ( C57BL/6J ) mice fed regular chow or 45% high-fat enriched diet（HFD）for 22 weeks respectively. The insulin secretion function indicated in isolated mouse islets with Hydroperoxide（H2O2）and CCR5 mAb treatment by glucose stimulate insulin secretion was examined. Additionally, ROS production by NBT reduction was also measured in RIN-m5F cell with palmitic acid and CCR5 antagonist cotreatment.
Cell viability were analyzed by MTT assay in isolated islet and RIN-m5F insulin secreting cells.
Results:
The high-fat-induced body weight gain was significantly decreased in those combined with Maraviroc treatment, but food intake remained similar. Maraviroc significantly improved the impaired OGTT. Moreover, the augmented levels of TNF-α, IFN-γ and leptin in adipocyte-derived conditional medium isolated from epididymal fat of HFD were markedly suppressed in those co-treated with Maraviroc. In addition, the increased adipocyte size in HFD was markedly decreased in those with Maraviroc administration.
As compared with wild-type mice, the islet size was smaller and the islet number was less in CCR5KO mice on the normal-chow diet ( NCD ). The islet macrophage and T-cell infiltration were significantly decreased in CCR5KO HFD mice .The pancreatic fat accumulation were significantly increased in HFD mice as compare to those in NCD mice, but were not different between CCR5KO and WT mice. The glucose-stimulated insulin secretion were suppressed while islets were treated with H2O2, but were significantly reversed in those with CCR5 mAb co-administration and islets isolated from CCR5KO mice. The palmitate-induced ROS production was significantly decreased in those cotreated with CCR5 antagonist in RIN-m5F cells.
Conclusion:
Collectively, our data suggested that CCR5 mediated inflammatory pathway might play a pivotal role in obesity-associated impairment of pancreatic insulin secretion and cell survival . In addition, CCR5 antagonist might also attenuate adipose tissue inflammation and improve glucose tolerance in the state of diet-induced obesity.
|
|---|
