The prevalence of obesity has markedly increased over the last few decades not only in wealthy industrialized countries, but also in poor underdeveloped nations

Journal of Lipid Research Volume 52, 2011 873 Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc. The prevalence of obesity has markedly increased over the last few decades not only in wealthy industrialized countries, but also in poor underdeveloped nations ( 1 ). Obesity and overweight have adverse health effects and affect the risk and prognosis of many serious medical conditions, such as type 2 diabetes, coronary heart disease, high blood pressure, and some forms of cancer. Obesity causes excess fat accumulation not only in various tissues, particularly adipose tissues, but also in other insulin-responsive organs such as the skeletal muscle and liver, predisposing one to the development of insulin resistance ( 2–5 ). However, the molecular mechanisms underlying insulin resistance and obesity have not been fully clarifi ed, and effective therapeutic approaches are currently of general interest. Peroxisome proliferator-activated receptors (PPAR) a , g , and d are FA-activated nuclear transcription factors that control mRNA expression of numerous genes involved in energy metabolism ( 6–8 ). In particular, PPAR a is expressed mostly in tissues with high rates of FA oxidation and peroxisomal metabolism ( 9 ), such as the liver, brown fat, and heart ( 10–12 ). In these tissues, PPAR a regulates mRNA expression of genes involved in FA oxidation, and synthetic PPAR a agonists, such as fi brates, Abstract Peroxisome proliferator-activated receptor (PPAR ) is a dietary lipid sensor, whose activation results in hypolipidemic effects. In this study, we investigated whether PPAR activation affects energy metabolism in white adipose tissue (WAT). Activation of PPAR by its agonist (bezafi brate) markedly reduced adiposity in KK mice fed a high-fat diet. In 3T3-L1 adipocytes, addition of GW7647, a highly specifi c PPAR agonist, during adipocyte differentiation enhanced glycerol-3-phosphate dehydrogenase activity, insulin-stimulated glucose uptake, and adipogenic gene expression. However, triglyceride accumulation was not increased by PPAR activation. PPAR activation induced expression of target genes involved in FA oxidation and stimulated FA oxidation. In WAT of KK mice treated with bezafi brate, both adipogenic and FA oxidation-related genes were signifi cantly upregulated. These changes in mRNA expression were not observed in PPAR -defi cient mice. Bezafi brate treatment enhanced FA oxidation in isolated adipocytes, suppressing adipocyte hypertrophy. Chromatin immunoprecipitation (ChIP) assay revealed that PPAR was recruited to promoter regions of both adipogenic and FA oxidation-related genes in the presence of GW7647 in 3T3L1 adipocytes. These fi ndings indicate that the activation of PPAR affects energy metabolism in adipocytes, and PPAR activation in WAT may contribute to the clinical effects of fi brate drugs. —Goto, T., J-Y. Lee, A. Teraminami, Y-I. Kim, S. Hirai, T. Uemura, H. Inoue, N. Takahashi, and T. Kawada. Activation of peroxisome proliferator-activated receptor-alpha stimulates both differentiation and fatty acid oxidation in adipocytes. J. Lipid Res. 2011. 52: 873–884.