Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner

High-fat diet (HFD) induces low-grade chronic inflammation and insulin resistance. However, little is known about the mechanism underlying HFD-induced chronic inflammation in peripheral insulin-responsive tissues. Here, we show that colonic pro-inflammatory macrophages regulate insulin sensitivity under HFD conditions. To investigate the pathophysiological role of colonic macrophages, we generated macrophage-specific chemokine (C-C Motif) receptor 2 (Ccr2) knockout (M-Ccr2KO) and intestinal epithelial cell-specific tamoxifen-inducible Ccl2 knockout (Vil-Ccl2KO) mice. Both strains exhibited similar body weight to control under HFD. However, they exhibited decreased infiltration of colonic pro-inflammatory macrophages, decreased intestinal permeability, and inactivation of the colonic inflammasome. Interestingly, they showed significantly improved glucose tolerance and insulin sensitivity with decreased chronic inflammation of adipose tissue. Therefore, inhibition of pro-inflammatory macrophage infiltration prevents HFD-induced insulin resistance and could be a novel therapeutic approach for type 2 diabetes. [Display omitted] •HFD-induced inflammatory changes occur earlier in the colon than adipose tissues•Colonic inflammatory macrophages increase intestinal permeability•HFD induces inflammasome activation in colonic macrophages•Inhibition of colonic macrophage recruitment prevents insulin resistance Kawano et al. reveal that the colon is the first tissue to respond to high-fat diet, with increased Ccl2 expression in intestinal epithelial cells leading to the recruitment of pro-inflammatory macrophages, increased gut permeability, and inflammasome activation, ultimately resulting in inflammation and insulin resistance in adipose tissue.