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

Abstract

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.

Insulin resistance causes inflammation in adipose tissue

“…Tnfa expression did not increase in mice at 4 or 10 weeks of a HFD (Supplemental Figure 5D). These findings are consistent with previous reports showing that mice develop adipose and systemic insulin resistance within several days to 4 weeks of a HFD (44,45), whereas the number of M1 macrophages in WAT increases only within 8 to 10 weeks of a HFD (10,15,45,46). The finding that HFD-induced insulin resistance precedes the accumulation of M1 macrophages is consistent with our above conclusion that insulin resistance leads to inflammation.…”

Dietary Milk Sphingomyelin Reduces Systemic Inflammation in Diet-Induced Obese Mice and Inhibits LPS Activity in Macrophages

“…These effects were mediated by early induction of CCL2 in intestinal epithelial cells, which attracted pro-inflammatory macrophages to colon tissue [9]. In this study, although we observed significantly greater colon CCL2 mRNA expression with milk SM intake, we did not observe any significant changes between groups in gene expression of gut barrier markers or macrophage infiltration/inflammation in colon and mesenteric adipose tissues.…”

“…Recently, chronic feeding of HFD to mice was shown to increase colonic pro-inflammatory macrophages and gut inflammation, which promoted LPS translocation, insulin resistance, and adipose tissue inflammation [9]. These effects were mediated by early induction of CCL2 in intestinal epithelial cells, which attracted pro-inflammatory macrophages to colon tissue [9].…”

“…Toll-like receptor 4 signaling then activates the nuclear factor-kappa B (NF-κb) transcription factor resulting in the production of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) [3]. Macrophages in the colon have been shown to be the first pro-inflammatory immune responders to an HFD [9]; thus, inhibiting LPS translocation and the subsequent inflammatory responses of macrophages shows great potential in reducing the detrimental effects of a diet rich in fat and cholesterol.…”

Prophylactic Oral Administration of Magnesium Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice through a Decrease of Colonic Accumulation of P2X7 Receptor-Expressing Mast Cells

“…38) Since macrophages are representative cells expressing P2X7R highly, [9][10][11][12] and Kurashima et al, demonstrated that mast cells treated with ATP showed the expression of chemokines such as Ccl2, 16) it is suggested that administration of magnesium might inhibit the development of high-fat diet-induced insulin resistance, leading to prevention of onset of lifestyle-related type II diabetes mellitus.…”