Distinct role of complement anaphylatoxin receptors C5aR and C3aR in obese adipose tissue inflammation and insulin resistance

Obese adipose tissue (AT) inflammation contributes critically to development of insulin resistance. It is characterized by the accumulation of macrophages in the obese AT and their polarization into the M1 pro-inflammatory macrophage subtype. The complement system is a major pro-inflammatory system and has been implicated in metabolic disease. Here, we compared the effects of the receptors for complement anaphylatoxins C5a and C3a, C5aR and C3aR, respectively, and their role in obesity, insulin resistance and AT inflammation. We engaged the model of diet-induced obesity by feeding mice a high fat diet (HFD) or a normal diet (ND) and found that expression of C5aR and C3aR was significantly upregulated in the obese AT, as compared to lean AT. Additionally, C5a was present in obese AT in the proximity of macrophage-rich crown-like structures. C5aR- or C3aR-deficiency did not affect weight gain in diet-induced obesity. Obese C5aR-/- as well as C3aR-/- mice displayed improved systemic insulin sensitivity, which was associated with mildly improved glucose tolerance in the C5aR-/- mice. In addition to the improved systemic insulin sensitivity, obese C5aR-/- mice showed improved AT-, but not hepatic insulin sensitivity. In obese C5aR-/- mice, we found reduced accumulation of total and pro-inflammatory M1 macrophages in the obese AT, increased expression of IL-10 and decreased AT fibrosis. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and that both, C5aR and C3aR contribute to obesity-induced development of systemic insulin resistance.