Dipeptidyl peptidase-4 inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice.
Journal - American journal of physiology. Endocrinology and metabolism
Adipose tissue inflammation and reduced pancreatic ß cell function are key issues in the development of cardiovascular disease and progressive metabolic dysfunction in type 2 diabetes mellitus. The aim of this study was to determine the effect of the DPP-4 inhibitor sitagliptin on adipose tissue and pancreatic islet inflammation in a diet-induced obesity model. C57Bl/6J mice were placed on a high fat (60%kcal fat) diet for 12 weeks, with or without sitagliptin (0.4gm/kg) as a food admix. Sitagliptin significantly reduced fasting blood glucose by 21% as well as insulin by ~25%. Also, sitagliptin treatment significantly reduced body weight with no changes in overall body mass index or in the epididymal and retroperitoneal fat mass. However, sitagliptin treatment led to triple the number of small adipocytes while reducing the number of the very large adipocytes. Also, sitagliptin significantly reduced inflammation in the adipose tissue and pancreatic islet. Macrophage infiltration in adipose tissue evaluated by immunostaining for Mac-2 was reduced by Sit (p<0.01) as was the percentage of CD11b+/F4/80+ cells in the stromal vascular fraction (p<0.02). Sitagliptin also reduced adipocyte mRNA expression of inflammatory genes including IL-6, TNFa, IL-12(p35) and IL-12(p40) by 2.5 to 5-fold, as well as 12-lipoxygenase protein expression. Pancreatic islets were isolated from animals after treatments. Sitagliptin significantly reduced mRNA expression of the following inflammatory cytokines: MCP-1 (3.3-fold), IL-6 (2-fold), IL-12(p40) (2.2-fold), IL-12(p35)(5-fold)(p<0.01) and IP-10 (2-fold). Collectively the results indicate that sitagliptin has anti-inflammatory effects in adipose tissue and in pancreatic islets that accompany the insulinotropic effect.