High-fat diets cause insulin resistance despite an increase in muscle mitochondria.
It has been hypothesized that insulin resistance is mediated by a deficiency of mitochondria in skeletal muscle. In keeping with this hypothesis, high-fat diets that cause insulin resistance have been reported to result in a decrease in muscle mitochondria. In contrast, we found that feeding rats high-fat diets that cause muscle insulin resistance results in a concomitant gradual increase in muscle mitochondria. This adaptation appears to be mediated by activation of peroxisome proliferator-activated receptor (PPAR)delta by fatty acids, which results in a gradual, posttranscriptionally regulated increase in PPAR gamma coactivator 1alpha (PGC-1alpha) protein expression. Similarly, overexpression of PPARdelta results in a large increase in PGC-1alpha protein in the absence of any increase in PGC-1alpha mRNA. We interpret our findings as evidence that raising free fatty acids results in an increase in mitochondria by activating PPARdelta, which mediates a posttranscriptional increase in PGC-1alpha. Our findings argue against the concept that insulin resistance is mediated by a deficiency of muscle mitochondria.
Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Chad R
CR
Hancock
Dong-Ho
DH
Han
May
M
Chen
Shin
S
Terada
Toshihiro
T
Yasuda
David C
DC
Wright
John O
JO
Holloszy
D050153:Abdominal Fat / Q000187:drug effects; D000818:Animals; D001835:Body Weight; D004032:Diet / Q000009:adverse effects; D004041:Dietary Fats / Q000008:administration & dosage*; D005230:Fatty Acids, Nonesterified / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017208:Rats, Wistar; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D047494:PPAR delta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors