Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome

Toshiya Tanaka, Joji Yamamoto, Satoshi Iwasaki, Hiroshi Asaba, Hiroki Hamura, Yukio Ikeda, Mitsuhiro Watanabe, Kenta Magoori, Ryoichi X. Ioka, Keisuke Tachibana, Yuichiro Watanabe, Yasutoshi Uchiyama, Koichi Sumi, Haruhisa Iguchi, Sadayoshi Ito, Takefumi Doi, Takao Hamakubo, Makoto Naito, Johan Auwerx, Masashi YanagisawaTatsuhiko Kodama, Juro Sakai

Research output: Contribution to journalArticle

657 Citations (Scopus)

Abstract

In this study, we defined the role of peroxisome proliferator-activated receptor β/δ (PPARδ) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARδ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARδ controls fatty acid oxidation by regulating genes involved in fatty acid transport, β-oxidation, and mitochondrial respiration. Similar PPARδ-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid β-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid β-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARδ is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

Original languageEnglish
Pages (from-to)15924-15929
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number26
DOIs
Publication statusPublished - 2003 Dec 23

Keywords

  • Insulin resistance
  • Obesity
  • PGC-1α
  • Pancreatic β-cell
  • Thermogenesis

ASJC Scopus subject areas

  • General

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    Tanaka, T., Yamamoto, J., Iwasaki, S., Asaba, H., Hamura, H., Ikeda, Y., Watanabe, M., Magoori, K., Ioka, R. X., Tachibana, K., Watanabe, Y., Uchiyama, Y., Sumi, K., Iguchi, H., Ito, S., Doi, T., Hamakubo, T., Naito, M., Auwerx, J., ... Sakai, J. (2003). Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proceedings of the National Academy of Sciences of the United States of America, 100(26), 15924-15929. https://doi.org/10.1073/pnas.0306981100