Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.
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.
Tanaka
Toshiya
T
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
Yamamoto
Joji
J
Iwasaki
Satoshi
S
Asaba
Hiroshi
H
Hamura
Hiroki
H
Ikeda
Yukio
Y
Watanabe
Mitsuhiro
M
Magoori
Kenta
K
Ioka
Ryoichi X
RX
Tachibana
Keisuke
K
Watanabe
Yuichiro
Y
Uchiyama
Yasutoshi
Y
Sumi
Koichi
K
Iguchi
Haruhisa
H
Ito
Sadayoshi
S
Doi
Takefumi
T
Hamakubo
Takao
T
Naito
Makoto
M
Auwerx
Johan
J
Yanagisawa
Masashi
M
Kodama
Tatsuhiko
T
Sakai
Juro
J
D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004798:Enzymes / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism; D008099:Liver / Q000502:physiology; D008297:Male; D024821:Metabolic Syndrome / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D010084:Oxidation-Reduction; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000187:drug effects
D004798:Enzymes; D005230:Fatty Acids, Nonesterified; C425931:GW 501516; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors; D004121:Dimethyl Sulfoxide