Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.

Abstract

In this study, we defined the role of peroxisome proliferator-activated receptor beta/delta (PPARdelta) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARdelta subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARdelta controls fatty acid oxidation by regulating genes involved in fatty acid transport, beta-oxidation, and mitochondrial respiration. Similar PPARdelta-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid beta-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 beta-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 PPARdelta 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.

• Authors: 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 Yanagisawa, Tatsuhiko Kodama, Juro Sakai
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 26 Pg. 15924-9 (Dec 23 2003) ISSN: 0027-8424 [Print] United States
• PMID: 14676330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzymes
• Fatty Acids, Nonesterified
• GW 501516
• Receptors, Cytoplasmic and Nuclear
• Thiazoles
• Transcription Factors
• Dimethyl Sulfoxide

Topics

• Animals
• Dimethyl Sulfoxide (pharmacology)
• Enzymes (genetics)
• Fatty Acids, Nonesterified (metabolism)
• Insulin Resistance (physiology)
• Lipid Metabolism
• Liver (physiology)
• Male
• Metabolic Syndrome (prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Muscle, Skeletal (drug effects, physiology)
• Oxidation-Reduction
• Rats
• Receptors, Cytoplasmic and Nuclear (agonists, drug effects)
• Thiazoles (pharmacology)
• Transcription Factors (agonists, drug effects)