A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle.
Obesity and type 2 diabetes have been associated with a high-fat diet (HFD) and reduced mitochondrial mass and function. We hypothesized a HFD may affect expression of genes involved in mitochondrial function and biogenesis. To test this hypothesis, we fed 10 insulin-sensitive males an isoenergetic HFD for 3 days with muscle biopsies before and after intervention. Oligonucleotide microarray analysis revealed 297 genes were differentially regulated by the HFD (Bonferonni adjusted P < 0.001). Six genes involved in oxidative phosphorylation (OXPHOS) decreased. Four were members of mitochondrial complex I: NDUFB3, NDUFB5, NDUFS1, and NDUFV1; one was SDHB in complex II and a mitochondrial carrier protein SLC25A12. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC1) alpha and PGC1beta mRNA were decreased by -20%, P < 0.01, and -25%, P < 0.01, respectively. In a separate experiment, we fed C57Bl/6J mice a HFD for 3 weeks and found that the same OXPHOS and PGC1 mRNAs were downregulated by approximately 90%, cytochrome C and PGC1alpha protein by approximately 40%. Combined, these results suggest a mechanism whereby HFD downregulates genes necessary for OXPHOS and mitochondrial biogenesis. These changes mimic those observed in diabetes and insulin resistance and, if sustained, may result in mitochondrial dysfunction in the prediabetic/insulin-resistant state.
Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
Lauren M
LM
Sparks
Hui
H
Xie
Robert A
RA
Koza
Randall
R
Mynatt
Matthew W
MW
Hulver
George A
GA
Bray
Steven R
SR
Smith
D000328:Adult; D000818:Animals; D015992:Body Mass Index; D004272:DNA, Mitochondrial / Q000187:drug effects / Q000235:genetics*; D048909:Diabetes Complications / Q000209:etiology / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000517:prevention & control; D004041:Dietary Fats / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption; D016133:Polymerase Chain Reaction
D004272:DNA, Mitochondrial; D004041:Dietary Fats