Abstract 5106: C-c Chemokine Receptor 2 Inhibitor Ameliorates Diet-induced Insulin Resistance and Hepatic Steatosis in Mice
Visceral obesity and insulin resistance are 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 by Mφ infiltration through MCP-1/CCR2 is considered to play a pivotal role in the development of visceral obesity and insulin resistance. However, the effect of postnatal inhibition of CCR2 on the development of diet-induced obesity (DIO) and insulin resistance remains unclear. To further explore the role of CCR2 in the development of visceral obesity and its associated metabolic disorders, we studied the effect of pharmacological inhibition of CCR2 before the onset of DIO in C57BL/6 mice. To study the effect of CCR2 inhibition, C57BL/6 mice were fed a high fat and high sugar diet with or without propagermanium (Pro, dose of 5mg and 50mg/kg/day), as a CCR2 inhibitor for 12 weeks from 6 weeks of age. At the end of study the gene expression of F4/80 and CD11c was reduced by 50%, while that of IL-10 and MGL-1 was increased by 2-fold in white adipose tissue (WAT), indicating that Pro suppressed adipose tissue Mφ accumulation and shifted the infiltration of pro-inflammatory M1 Mφ to anti-inflammatory M2 Mφ. These data are consistent with a marked reduction of pro-inflammatory cytokine, TNF-α by Pro by 50% in WAT and liver. Diet-induced hypoadiponectinemia and hyperleptinemia were also improved by Pro treatment. Further, Pro treatment ameliorated insulin sensitivity and glucose tolerance, resulting in a marked reduction of plasma glucose and insulin level. Finally, Pro treatment decreased hepatic triglyceride contents by 45% in DIO mice. In conclusion, Pro improved obesity and its associated metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing infiltration of pro-inflammatory M1 Mφ into WAT. Our data also implicate that CCR2 contributes to DIO and type 2 diabetes by accelerating adipose tissue inflammation, and that Pro may be a beneficial drug for the treatment of such metabolic disorders by blocking CCR2-mediated inflammation.