title: 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.
authors: Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Yoshinaga
authors: Y
authors: Kawano
authors: Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address: jnakae5330@a7.keio.jp.
authors: Jun
authors: J
authors: Nakae
authors: Department of Human Genetics, National Center for Child Health and Development, Tokyo 157-0074, Japan.
authors: Nobuyuki
authors: N
authors: Watanabe
authors: Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Tetsuhiro
authors: T
authors: Kikuchi
authors: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Sanshiro
authors: S
authors: Tateya
authors: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Endocrinology and Metabolism, Chibune General Hospital, Osaka 555-0011, Japan.
authors: Yoshikazu
authors: Y
authors: Tamori
authors: Animal Resource Development Unit, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan; Genetic Engineering Team, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
authors: Mari
authors: M
authors: Kaneko
authors: Genetic Engineering Team, Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan.
authors: Takaya
authors: T
authors: Abe
authors: Department of Human Genetics, National Center for Child Health and Development, Tokyo 157-0074, Japan.
authors: Masafumi
authors: M
authors: Onodera
authors: Division of Endocrinology, Metabolism, and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors: Hiroshi
authors: H
authors: Itoh
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D003106:Colon / Q000473:pathology*; D059305:Diet, High-Fat; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D017353:Gene Deletion; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000187:drug effects; D010539:Permeability; D054390:Receptors, CCR2 / Q000378:metabolism*
chemical_list: D018932:Chemokine CCL2; D058847:Inflammasomes; D007328:Insulin; D054390:Receptors, CCR2