A potential link between muscle peroxisome proliferator- activated receptor-alpha signaling and obesity-related diabetes.
The role of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in the development of insulin-resistant diabetes was evaluated using gain- and loss-of-function approaches. Transgenic mice overexpressing PPARalpha in muscle (MCK-PPARalpha mice) developed glucose intolerance despite being protected from diet-induced obesity. Conversely, PPARalpha null mice were protected from diet-induced insulin resistance in the context of obesity. In skeletal muscle, MCK-PPARalpha mice exhibited increased fatty acid oxidation rates, diminished AMP-activated protein kinase activity, and reduced insulin-stimulated glucose uptake without alterations in the phosphorylation status of key insulin-signaling proteins. These effects on muscle glucose uptake involved transcriptional repression of the GLUT4 gene. Pharmacologic inhibition of fatty acid oxidation or mitochondrial respiratory coupling prevented the effects of PPARalpha on GLUT4 expression and glucose homeostasis. These results identify PPARalpha-driven alterations in muscle fatty acid oxidation and energetics as a potential link between obesity and the development of glucose intolerance and insulin resistance.
Finck
Brian N
BN
Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Bernal-Mizrachi
Carlos
C
Han
Dong Ho
DH
Coleman
Trey
T
Sambandam
Nandakumar
N
LaRiviere
Lori L
LL
Holloszy
John O
JO
Semenkovich
Clay F
CF
Kelly
Daniel P
DP
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D018076:DNA, Complementary / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000166:cytology / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
D018076:DNA, Complementary; D005227:Fatty Acids; D007328:Insulin; D047493:PPAR alpha; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose; D010100:Oxygen