Abstract 5866: Dipeptidyl Peptidase-4 (DDP-4) Inhibitor Sitagliptin Inhibits Inflammation in Visceral and Peri-aortic Fat in a Mouse Model of Obesity
Visceral adipose tissue inflammation is a key mechanism in the development of cardiovascular disease and progressive metabolic dysfunction in obesity. New evidence also shows that peri-vascular fat contributes to vascular dysfunction. The aim of this study was to determine the effect of sitagliptin (Sit) on adipose tissue inflammation and remodelling. 8 week old C57Bl6 mice (n=8 –10/group) were placed on either high fat (HF-60%kcal fat) or low fat (LF-11% kcal fat) isocaloric diets for 12 weeks, with or without Sit (4g/kg) as a food admix. HF diet alone induced glucose intolerance. Sit significantly reduced fasting blood glucose by 21% in the HF group. Also, Sit treatment significantly reduced body weight by 25%in HF mice, with no changes in total visceral fat. Adipocyte average size or number was not changed by Sit. However Sit significantly increased the number of small adipocytes (area< 500μm2) while reducing the number of the very large adipocytes (area>5,000μm2) in both HF and LF groups. Interestingly, Sit reduced apoptosis in visceral fat in the HF group. These results suggest that Sit may have an important role in adipose tissue remodeling. Immunostaining for Mac-2 in epididymal fat showed a significant reduction by Sit in the HF group (p<0.01). Real-time PCR data showed that Sit significantly reduced mRNA expression of MCP-1 (p<0.01), TNFα and IL-12(p35) by 4.5 to 5-fold in the visceral fat of HF mice. Sit also reduced by 3.5-fold MCP-1 expression in peri-aortic fat (p<0.01) in the HF group. We studied expression of 12-lipoxygenase(12-LO), a highly pro-inflammatory protein linked to atherosclerosis. Immunostaining indicated a significant reduction (p<0.01) in 12-LO expression in both visceral and peri-aortic fat in the Sit treated HF group. Collectively the results indicate that Sit induces visceral adipose tissue remodelling without changing total fat mass and has selective anti-inflammatory effects on visceral and peri-aortic adipose tissues. These new results suggest that DPP4 inhibition with Sit has actions that could translate into reduced cardiovascular disease in states of visceral adiposity.