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

Yoshinaga Kawano, Jun Nakae, Nobuyuki Watanabe, Tetsuhiro Kikuchi, Sanshiro Tateya, Yoshikazu Tamori, Mari Kaneko, Takaya Abe, Masafumi Onodera, Hiroshi Itoh

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)295-310
Number of pages16
JournalCell Metabolism
Volume24
Issue number2
DOIs
Publication statusPublished - 2016 Aug 9

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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