GSE119633
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 preadipocytes restrains adipogenic differentiation. FAP-mediated matrix remodeling also alters lipid metabolism in part by regulating mTOR signaling. Together, via these mechanisms, FAP confers resistance to diet-induced obesity. The critical role of ECM remodeling in regulating obesity offers new potential targets for therapy. Overall design: Two or three biological replicates were analyzed for each of 4 conditions (two genotypes; two diets per genotype)