Targeting inhibition of CCR5 on improving obesity-associated insulin resistance and impairment of pancreatic insulin secretion in high fat-fed rodent models

doi:10.1016/j.ejphar.2020.173703

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標題:	Targeting inhibition of CCR5 on improving obesity-associated insulin resistance and impairment of pancreatic insulin secretion in high fat-fed rodent models
作者:	Chan, Pei-Chi Liao, Min-Tser Lu, Chieh-Hua Tian, Yu-Feng Hsieh, Po-Shiuan
貢獻者:	Natl Def Med Ctr NDMC, Dept Physiol & Biophys Taoyuan Armed Forces Gen Hosp, Dept Pediat Triserv Gen Hosp, Dept Pediat NDMC, Triserv Gen Hosp, Dept Internal Med, Div Endocrinol & Metab Chia Nan Univ Pharm & Sci, Chi Mei Med Ctr, Dept Surg, Div Gen Surg, Yung Kung Campus NDMC, Inst Prevent Med Triserv Gen Hosp, Dept Med Res
關鍵字:	CCR5 Reactive oxygen species Insulin secretion Obesity High fat feeding
日期:	2021
上傳時間:	2023-11-11 11:58:16 (UTC+8)
出版者:	ELSEVIER
摘要:	Obesity is closely linked with type 2 diabetes and the effective therapies on obesity-associated diabetes are under development. The aim of this study was undertaken to investigate whether the inhibition of the augmented CCR5-mediated signaling could be a common target for treatment of obesity-associated insulin resistance and impairment of pancreatic insulin secretion in high-fat diet (HFD) fed rats and CCR5 knockout mice and also in isolated islets and RIN-m5F cells. Conducted with SD rats, HFD-induced body weight gain was significantly decreased in those combined with Maraviroc treatment, but food intake remained similar compared to control. Maraviroc also significantly improved the impaired oral glucose tolerance test (OGTT). As compared with wild-type mice, CCR5 deletion significantly attenuated the HFD-induced increases in glucose area under curve of OGTT and the value of HOMA-IR as well as plasma lipid profile. It also reversed the HFD-suppressed gene expressions of GLUT4 and IRS-1 in adipose tissue. On the other hand, the HFD-associated islet macrophage and T-cell infiltration were significantly decreased in CCR5 KO mice. H2O2 significantly suppressed glucose-stimulated insulin secretion (GSIS) is isolated islets, which were significantly reversed in those cotreated with CCR5 mAb. H2O2 failed to change GSIS in those of CCR5 KO mice. The palmitate-induced reactive oxygen species production was significantly decreased in those cotreated with CCR5 antagonist in RIN-m5F cells. Collectively, it is suggested that targeting inhibition of the CCR5 mediated inflammatory pathway could not only improve obesity-associated insulin resistance but also directly alleviate pancreatic beta-cell dysfunction.
關聯:	EUR J PHARMACOL, v.891, 173703
顯示於類別:	[保健營養系(所) ] 期刊論文

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