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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2195.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Inhibition of CCR2 Ameliorates Insulin Resistance and Hepatic Steatosis in db/db Mice

Yukinori Tamura; Masayuki Sugimoto; Toshinori Murayama; Yukihiko Ueda; Hiroshi Kanamori; Koh Ono; Hiroyuki Ariyasu; Takashi Akamizu; Toru Kita; Masayuki Yokode; Hidenori Arai

From the Departments of Clinical Innovative Medicine (Y.T., M.S., T.M., M.Y.), Cardiovascular Medicine (Y.U., K.O., T.K.), Nephrology (H.K.), and Geriatric Medicine (H.A.), Kyoto University Graduate School of Medicine (H.A., T.A.), Translational Research Center, Kyoto University Hospital (H.A., T.A.), Japan.

Correspondence to Hidenori Arai, MD, PhD, Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail harai{at}kuhp.kyoto-u.ac.jp

Objective— Recently, adipose tissue inflammation induced by macrophage infiltration through MCP-1/C-C chemokine receptor-2 (CCR2) pathway is considered to play a role in the development of visceral obesity and insulin resistance. In the present study, to further examine the role of CCR2 in the development of obesity and type 2 diabetes, we studied the effect of pharmacological inhibition of CCR2 from the early stage of obesity in db/db mice.

Methods and Results— Db/+m (lean control) and db/db mice were fed with a standard diet with or without 0.005% propagermanium, as a CCR2 inhibitor for 12 weeks from 6 weeks of age. Propagermanium treatment decreased body weight gain, visceral fat accumulation, and the size of adipocytes only in db/db mice. Further, propagermanium suppressed macrophage accumulation and inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance and insulin sensitivity, and decreased hepatic triglyceride contents in db/db mice.

Conclusions— Propagermanium improved obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve obesity and type 2 diabetes by interfering adipose tissue inflammation, and that propagermanium may be a beneficial drug for the treatment of the metabolic syndrome.

To examine the role of CCR2 in the development of obesity and type 2 diabetes, we studied the effect of inhibition of CCR2 by propagermanium treatment in db/db mice. Propagermanium improved obesity-related metabolic disorders, implicating that inhibition of CCR2 improves obesity and type 2 diabetes by interfering adipose tissue inflammation.

Key Words: cytokines • diabetes mellitus • insulin resistance • macrophages • receptors