Peroxisome-Proliferator-Activated Receptor δ Activates Fat Metabolism to Prevent Obesity

1 Gene Expression Laboratory tional level, how this process is controlled, in particular 2 Howard Hughes Medical Institute how fuel oxidation and energy uncoupling is integrated, The Salk Institute is not well understood. elements in the promoter region of target genes. The Seoul 151-747 PPAR subgroup comprises three closely related mem-Korea bers: PPAR␣, ␥, and ␦. They are activated by a variety of fatty acids, fatty acid derivatives, and synthetic compounds. Each member displays a tissue-selective ex-Summary pression pattern, with PPAR␣ and PPAR␥ predominantly in the liver and adipose tissue, respectively, and PPAR␦ In contrast to the well-established roles of PPAR␥ and in many tissues. Genetic and pharmacological studies PPAR␣ in lipid metabolism, little is known for PPAR␦ have revealed distinct roles of PPAR␥ and PPAR␣ in lipid in this process. We show here that targeted activation metabolism. PPAR␥ serves as an essential regulator for of PPAR␦ in adipose tissue specifically induces ex-adipocyte differentiation and promotes lipid storage in pression of genes required for fatty acid oxidation and mature adipocytes by increasing the expression of sev-energy dissipation, which in turn leads to improved eral key genes in this pathway (Rosen and Spiegelman, lipid profiles and reduced adiposity. Importantly, these 2001; Berger and Moller, 2002). These two important animals are completely resistant to both high-fat diet-functions of PPAR␥ in adipocytes are suggested to induced and genetically predisposed (Lepr db/db) obe-largely account for the insulin sensitizing effects of the sity. As predicted, acute treatment of Lepr db/db mice anti-diabetic thiazolidinediones (Yamauchi et al., 2001b). with a PPAR␦ agonist depletes lipid accumulation. In In contrast, PPAR␣ enhances fatty acid combustion in parallel, PPAR␦-deficient mice challenged with high-liver by upregulating genes encoding enzymes in ␤-oxi-fat diet show reduced energy uncoupling and are dation and hence mediates the hypolipidemic effects of prone to obesity. In vitro, activation of PPAR␦ in adipo-the fibrates (Reddy and Hashimoto, 2001; Berger and cytes and skeletal muscle cells promotes fatty acid Moller, 2002). While this PPAR␣-regulated ␤-oxidation oxidation and utilization. Our findings suggest that pathway in the liver plays a major role in generating PPAR␦ serves as a widespread regulator of fat burning ketone bodies to support general fuel needs during fast-and identify PPAR␦ as a potential target in treatment ing, similar mechanisms must exist within the peripheral of obesity and its associated disorders. tissues to enable local response to energy load and demands. Introduction The functions of PPAR␦ remain …