CCR5 Plays a Critical Role in Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Regulating Both Macrophage Recruitment and M1/M2 Status
- Hironori Kitade1,2,
- Kazuki Sawamoto1,2,
- Mayumi Nagashimada1,
- Hiroshi Inoue1,
- Yasuhiko Yamamoto3,
- Yoshimichi Sai2,
- Toshinari Takamura4,
- Hiroshi Yamamoto3,
- Ken-ichi Miyamoto2,
- Henry N. Ginsberg5,
- Naofumi Mukaida6,
- Shuichi Kaneko4 and
- Tsuguhito Ota1,4⇓
- 1Frontier Science Organization, Kanazawa University, Kanazawa, Ishikawa, Japan
- 2Department of Hospital Pharmacy, Kanazawa University, Kanazawa, Ishikawa, Japan
- 3Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
- 4Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
- 5Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York
- 6Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan
- Corresponding author: Tsuguhito Ota, .
C-C motif chemokine receptor (CCR)2 and its ligand, monocyte chemoattractant protein (MCP)-1, are pivotal for adipose tissue macrophage (ATM) recruitment and the development of insulin resistance. However, other chemokine systems also may play a role in these processes. In this study, we investigated the role of CCR5 in obesity-induced adipose tissue inflammation and insulin resistance. We analyzed expression levels of CCR5 and its ligands in white adipose tissue (WAT) of genetically (ob/ob) and high-fat (HF) diet–induced obese (DIO) mice. Furthermore, we examined the metabolic phenotype of Ccr5−/− mice. CCR5 and its ligands were markedly upregulated in WAT of DIO and ob/ob mice. Fluorescence-activated cell sorter analysis also revealed that DIO mice had a robust increase in CCR5+ cells within ATMs compared with chow-fed mice. Furthermore, Ccr5−/− mice were protected from insulin resistance, glucose intolerance, and hepatic steatosis induced by HF feeding. The effects of loss of CCR5 were related to both reduction of total ATM content and an M2-dominant shift in ATM polarization. It is noteworthy that transplantation of Ccr5−/− bone marrow was sufficient to protect against impaired glucose tolerance. CCR5 plays a critical role in ATM recruitment and polarization and subsequent development of insulin resistance.
- Received October 28, 2011.
- Accepted February 29, 2012.
- © 2012 by the American Diabetes Association.
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