Loss of C3a and C5a receptors promotes adipocyte browning and attenuates diet-induced obesity via activating inosine/A2aR pathway

Complement activation is thought to underline the pathologic progression of obesity-related metabolic dis-orders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identify comple-ment C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance in male mice. Loss of C3aR and C5aR in combination, more than individually, increases cold-induced adipocyte browning and attenuates diet-induced obesity in male mice. Mechanistically, loss of C3aR and C5aR increases regulatory T cell (Treg) accumulation in the subcutaneous white adipose tissue during cold exposure or high-fat diet. Activated Tregs produce adenosine, which is converted to inosine by adipocyte-derived adenosine deaminases. Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor. These data reveal a regulatory mechanism of complement in controlling adaptive thermogenesis and suggest that targeting the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity-related metabolic diseases.

Automated summary

This study identifies complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches in controlling adipocyte browning and energy balance. Loss of C3aR and C5aR promotes cold-induced adipocyte browning and reduces diet-induced obesity. Mechanistically, loss of C3aR and C5aR increases regulatory T cell accumulation in subcutaneous white adipose tissue, leading to the production of adenosine that promotes adipocyte browning through the adenosine A2a receptor.