Abstract
Complement activation is thought to underline the pathologic progression of obesity-related metabolic disorders; however, its role in adaptive thermogenesis has scarcely been explored. Here, we identified complement C3a receptor (C3aR) and C5a receptor (C5aR) as critical switches to control adipocyte browning and energy balance. We found that loss of C3aR and C5aR in combination, more than individually, increased cold-induced adipocyte browning and attenuated diet-induced obesity. Mechanistically, loss of C3aR and C5aR increased regulatory T cells (Tregs) accumulation in the subcutaneous white adipose tissue (sWAT) during cold exposure or high fat diet (HFD). Activated Tregs produced adenosine, which was converted to inosine by adipocyte-derived adenosine deaminases (ADA). Inosine promotes adipocyte browning in a manner dependent on activating adenosine A2a receptor (A2aR). These data reveal a novel regulatory mechanism of complement in controlling adaptive thermogenesis and suggest targeting of the C3aR/C5aR pathways may represent a therapeutic strategy in treating obesity and metabolic diseases.
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