TY - JOUR
T1 - Colonic Pro-inflammatory Macrophages Cause Insulin Resistance in an Intestinal Ccl2/Ccr2-Dependent Manner
AU - Kawano, Yoshinaga
AU - Nakae, Jun
AU - Watanabe, Nobuyuki
AU - Kikuchi, Tetsuhiro
AU - Tateya, Sanshiro
AU - Tamori, Yoshikazu
AU - Kaneko, Mari
AU - Abe, Takaya
AU - Onodera, Masafumi
AU - Itoh, Hiroshi
N1 - Funding Information:
We thank Dr. Eric G. Pamer (Memorial Sloan-Kettering Cancer Center) for providing the Ccl2-RFP flox/flox mice, Dr. Sylvie Robine (Institut Curie-CNRS) for providing Vil-Cre-ER T2 , and Dr. Shinichiro Sawa (The University of Tokyo) and Drs. Arata Itoh and Junichiro Irie (Keio University School of Medicine) for technical advice. This work was supported by a JSPS KAKENHI Grant-in-Aid for Young Scientists (B), grant number 26860338, to Y.K. by Scientific Research on Innovative Areas; a MEXT Grant-in-Aid Project “Crosstalk between transcriptional control and energy pathways, mediated by hub metabolites,” grant number 26116724, to J.N.; JSPS KAKENHI 26670509 to J.N., a grant from Nippon Boehringer Ingelheim Co., Ltd. to H.I., a Junior Scientist Development Grant supported by Novo Nordisk Pharma Ltd to Y.K., and a Banyu Foundation Research Grant to Y.K.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/8/9
Y1 - 2016/8/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cmet.2016.07.009
DO - 10.1016/j.cmet.2016.07.009
M3 - Article
C2 - 27508875
AN - SCOPUS:84991048144
SN - 1550-4131
VL - 24
SP - 295
EP - 310
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -
