Abstract

Objective: Significant new data suggests that metabolic disorders such as diabetes, obesity and atherosclerosis all posses an important inflammatory component. Infiltrating macrophages contribute to both tissue-specific and systemic inflammation which promotes insulin resistance. The complement cascade is involved in the inflammatory cascade initiated by the innate and adaptive immune response. A mouse genomic F2 cross biology was performed and identified several causal genes linked to Type 2 Diabetes including the complement pathway.

Research Design and Methods: We therefore sought to investigate the effect of a C3a receptor (C3aR) deletion on insulin resistance, obesity and macrophage function utilizing both normal diet (ND) and a diet-induced obesity mouse model.

Results: We demonstrate that high C3aR expression is found in white adipose tissue (WAT) and increases upon high fat diet (HFD) feeding. Both adipocytes and macrophages within the WAT express significant amounts of the C3aR. C3aR^−/− mice on HFD are transiently resistant to diet-induced obesity during a 8 week period. Metabolic profiling suggests that they are also protected from HFD-induced insulin resistance and liver steatosis. C3aR^−/− mice had improved insulin sensitivity on both ND and HFD as seen by ITT and oGTT. Adipose tissue analysis revealed a striking decrease in macrophage infiltration with a concomitant reduction in both tissue and plasma pro-inflammatory cytokine production. Furthermore, C3aR^−/− macrophages polarized to the M1 phenotype showed a considerable decrease in pro-inflammatory mediators.

Conclusions: Overall, our results suggest that the C3aR in macrophages and potentially adipocytes plays an important role in adipose tissue homeostasis and insulin resistance.