Abstract 873: C-C chemokine receptor-2 Inhibitor Ameliorates Insulin Resistance And Hepatic Steatosis In Db/db Mice.
Visceral obesity and insulin resistance are thought to represent common underlying factors of the metabolic syndrome (MetS), which is associated with a chronic low-grade inflammatory state and cardiovascular disease. C-C chemokine receptor-2 (CCR2), known as a receptor for MCP-1, plays a role in monocyte/macrophage (Mϕ) recruitment and Mϕ-dependent inflammatory response. Recently, adipose tissue inflammation induced by Mϕ infiltration through MCP-1/CCR2 is considered to play a role in the development of visceral obesity and insulin resistance. Therefore, to further examine the role of CCR2 in the development of obesity and related metabolic disorders, we studied the effect of long-term inhibition of CCR2 before the onset of obesity in db/db mice. In this study, db/+m (lean control) and db/db mice were fed a standard diet with or without 0.005% propagermanium (Pro), as a CCR2 inhibitor for 12 weeks from 6 weeks of age. Pro treatment decreased body weight and visceral fat accumulation without affecting food intake only in db/db mice. The size of adipocytes was decreased by 40%, while the plasma adiponecitn concentration was increased by 30% in Pro-treated db/db mice. Epididymal fat pad histology and gene expression analysis showed that Pro treatment decreased adipose tissue Mϕ accumulation in db/db mice. Further, MCP-1 and TNF-α expression was reduced in adipose tissue of Pro-treated db/db mice by 65% and 60%, respectively, suggesting that Pro suppresses adipose tissue inflammation only in obese states. Pro treatment significantly reduced the fasting blood glucose and HbA1c, and markedly decreased plasma insulin concentrations. Pro also ameliorated glucose tolerance and insulin sensitivity in db/db mice. Finally, Pro decreased hepatic triglyceride contents in pro-treated db/db mice by 40% compared with those in non-treated db/db mice. In conclusion, Pro improved obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing adipose tissue inflammation. Our data implicates that CCR2 contributes to the development of obesity and type 2 diabetes by accelerating adipose tissue inflammation, and that Pro may be a promising drug for the treatment of MetS and for the prevention of cardiovascular disease.