Ceramide-FGF13 axis regulate nutrient sensing

Ceramide accumulation impairs adipocytes' ability to efficiently store and utilize nutrients, leading to energy and glucose homeostasis deterioration. Using a comparative transcriptomic screen, we identified the non-canonical, non-secreted fibroblast growth factor FGF13 as a ceramide-regulated factor that impairs adipocyte function. Obesity robustly induces FGF13 expression in adipose tissue in mice and humans and is positively associated with glycemic indices of type 2 diabetes. Pharmacological or genetic inhibition of ceramide biosynthesis reduces FGF13 expression. Using mice with loss and gain-of-function of FGF13, we demonstrate that FGF13 is both necessary and sufficient to impair energy and glucose homeostasis independent of ceramides. Mechanistically, FGF13 exerts these effects by inhibiting mitochondrial content and function, metabolic elasticity, and caveolae formation, which cumulatively impairs glucose utilization and thermogenesis. These studies suggest the therapeutic potential of targeting FGF13 to prevent and treat metabolic diseases. Overall design: To investigate the molecular targets of fgf13 in adipose tissue, RNA seq was performed on the adipose tissue obtained from obese control and Fgf13?Adipo [inducible (ieWAT and isWAT) and constitutive (sWAT and BAT)] mice fed a high fat diet for 20 weeks. Differentially gene expression analysis was done on RNA-Seq data obtained from obese control and obese Fgf13 knockout mice.