Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity.

In contrast to the well-established roles of PPARgamma and PPARalpha in lipid metabolism, little is known for PPARdelta in this process. We show here that targeted activation of PPARdelta in adipose tissue specifically induces expression of genes required for fatty acid oxidation and energy dissipation, which in turn leads to improved lipid profiles and reduced adiposity. Importantly, these animals are completely resistant to both high-fat diet-induced and genetically predisposed (Lepr(db/db)) obesity. As predicted, acute treatment of Lepr(db/db) mice with a PPARdelta agonist depletes lipid accumulation. In parallel, PPARdelta-deficient mice challenged with high-fat diet show reduced energy uncoupling and are prone to obesity. In vitro, activation of PPARdelta in adipocytes and skeletal muscle cells promotes fatty acid oxidation and utilization. Our findings suggest that PPARdelta serves as a widespread regulator of fat burning and identify PPARdelta as a potential target in treatment of obesity and its associated disorders.