F4/80hiCCR2hi macrophage infiltration into the intra-abdominal fat worsens the severity of experimental IBD in obese mice with DSS colitis

Abstract

Background & aims: Intra-abdominal fat is pathogenically involved in both type 2 diabetes and inflammatory bowel disease (IBD). However, little is known about the interrelationships between these two widespread and devastating diseases. The goal of this study is to investigate the effect of obesity in the severity of colitis and, in turn, examine the impact of IBD on glucose tolerance during obesity. In this context, we have explored the role of infiltrating macrophages in the severity of diabetes and IBD. Methods: The infiltration of macrophages and T cells into intra-abdominal WAT, liver and the colonic lamina propria was examined in db/db and lean mice after a 7-day dextran sodium sulfate (DSS) challenge by tissue fractionation and flow cytometry. Disease activity indices (DAI), weight loss and colonic histology were examined during the course of the DSS challenge, and colonic pro-inflammatory cytokine expression was quantified by real-time RT-PCR. To determine the impact of obesity and intestinal inflammation on glucose tolerance, mice were administered an intraperitoneal glucose tolerance test. Results: We found that obesity increases the severity of experimental IBD. Following a DSS challenge, obese mice express greater concentrations of colonic TNF-a mRNA than lean mice. In addition, experimental IBD in combination with obesity worsens glucose tolerance beyond the effect caused by obesity alone. F4/80hiCCR2hi macrophages infiltrate the lamina propria of mice with DSS colitis and the WAT of obese mice. Conclusions: Infiltration of F4/80hiCCR2hi macrophages into intra-abdominal fat worsens the severity of experimental IBD during obesity. In turn, experimental IBD in obese mice repressed skeletal muscle PPAR g and GLUT4 mRNA expression, upregulated MCP-1 and worsened type 2 diabetes.