FAP deficiency enhances thermogenesis and attenuates metabolic inflammation in diet-induced obesity

Objective: Fibroblast activation protein alpha (FAP) is expressed in normal adipose tissue and related to some pleiotropic metabolic regulators. However, the exact role and mechanism of FAP in obesity and related metabolic disorders are not well understood.Methods: FAP knockout mice were fed a normal diet or a high-fat diet (HFD) for 12 weeks. FAP knockout mice or wild-type mice treated with an FAP inhibitor were subjected to cold stress for 5 days.Results: FAP deficiency protected mice against HFD-induced obesity and obesity-associated metabolic dysfunction, including glucose intolerance, insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. Notably, FAP deficiency largely reversed obesity-induced adipose tissue macrophage accumulation and M1-M2 imbalance in white adipose tissue (WAT). Moreover, energy expenditure was significantly higher in FAP-deficient mice fed an HFD. Both FAP deficiency and inhibition increased cold tolerance through enhancing WAT beiging.Conclusions: This study demonstrated that FAP deficiency protects mice against diet-induced obesity and related metabolic dysfunction. Furthermore, the protective effects are probably mediated via the promotion of WAT beiging and suppression of inflammation. image