Fibroblast activation protein restrains adipogenic differentiation and regulates matrix-mediated mTOR signaling

Obesity is a risk factor for multiple diseases, including diabetes, cardiovascular disease, and cancer. Within obese adipose tissue, multiple factors contribute to creating a disease-promoting environment, including metabolic dysfunction, inflammation, and fibrosis. Recent evidence points to fibrotic responses, particularly extracellular matrix remodeling, in playing a highly functional role in the pathogenesis of obesity. Fibroblast activation protein plays an essential role in remodeling collagen-rich matrices in the context of fibrosis and cancer. We observed that FAP-null mice have increased weight compared to wild-type controls, and so investigated the role of FAP in regulating diet-induced obesity. Using genetically engineered mouse models and in-vitro cell-derived matrices, we demonstrate that FAP expression by pre-adipocytes restrains adipogenic differentiation. We further show that FAP-mediated matrix remodeling alters lipid metabolism in part by regulating mTOR signaling. The impact of FAP on adipogenic differentiation and mTOR signaling together confers resistance to diet-induced obesity. The critical role of ECM remodeling in regulating obesity offers new potential targets for therapy.