A High-Fat Diet Coordinately Downregulates Genes Required for Mitochondrial Oxidative Phosphorylation in Skeletal Muscle

TLDR

High‑fat diets are linked to obesity and type 2 diabetes and are associated with reduced mitochondrial mass and function in skeletal muscle. The study aimed to test whether a short‑term high‑fat diet alters the expression of genes involved in mitochondrial function and biogenesis. Ten insulin‑sensitive men received a 3‑day isoenergetic high‑fat diet with pre‑ and post‑intervention muscle biopsies, and a separate 3‑week high‑fat diet was given to C57Bl/6J mice for parallel analysis. Microarray analysis identified 297 differentially expressed genes, including six oxidative‑phosphorylation genes and PGC1α/β, all down‑regulated by the high‑fat diet, indicating that such a diet suppresses genes essential for OXPHOS and mitochondrial biogenesis and recapitulates changes seen in diabetes.

Abstract

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 γ coactivator-1 (PGC1) α and PGC1β 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 ∼90%, cytochrome C and PGC1α protein by ∼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.