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Metabolism

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

  1. Lauren M. Sparks,
  2. Hui Xie,
  3. Robert A. Koza,
  4. Randall Mynatt,
  5. Matthew W. Hulver,
  6. George A. Bray and
  7. Steven R. Smith
  1. From the Pennington Biomedical Research Center, Baton Rouge, Louisiana
  1. Address correspondence and reprint requests to Steven R. Smith, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808. E-mail: smithsr{at}pbrc.edu
Diabetes 2005 Jul; 54(7): 1926-1933. https://doi.org/10.2337/diabetes.54.7.1926
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    FIG. 1.

    HFD decreases mRNA for genes involved in OXPHOS in healthy young men and mice. A: Effect of a 3-day isoenergetic HFD (50% fat vs. 35% fat) in a cohort of healthy insulin-sensitive males (n = 10) at baseline and after intervention on the expression of genes in complex I (NDUFB3, NDUFB5, NDUFV1, and NDUFS1), complex II (SDHB), complex III (CYC1), complex IV (SURF1), and a mitochondrial carrier protein (SLC25A12). mRNA was quantified by quantitative RT-PCR. Data are shown as means ± SE and corrected for the expression of 18S and RPLP0. NDUFB3, NADH dehydrogenase (ubiquinone) one β subcomplex, 3; NDUFB5, NADH dehydrogenase (ubiquinone) one β subcomplex, 5; NDUFV1, NADH dehydrogenase (ubiquinone) flavoprotein 1; NDUFS1, NADH dehydrogenase (ubiquinone) Fe-S protein 1); SDHB, succinate dehydrogenase complex, subunit B; SLC25A12, solute carrier family 25 (mitochondrial carrier); CYC1, cytochrome c-1; SURF1, surfeit 1. B: Effect of a 21-day HFD (45% fat vs. 10% fat) in a cohort of C57Bl/6J mice (control, n = 6; HFD, n = 7) on genes in complex I (NDUFB3 AND NDUFB5), complex II (SDHB), complex III (CYC1), complex IV (SURF1), and a mitochondrial carrier protein (SLC25A12). Data are shown as means ± SE and corrected for the expression of cyclophilin B.

  • FIG. 2.
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    FIG. 2.

    HFD decreases expression of transcriptional cofactors involved in the regulation of OXPHOS expression and mitochondrial biogenesis in healthy young men and mice. A: Effect of a 3-day isoenergetic HFD (50% fat vs. 35% fat) in a cohort of healthy insulin-sensitive males (n = 10) at baseline and after intervention on the expression of genes involved in mitochondrial biogenesis. Data are shown as means ± SE and corrected for the expression of ribosomal protein, large, P0. NRF1, nuclear respiratory factor-1. B: Effect of a 21-day HFD (45% fat vs. 10% fat) in a cohort of C57Bl/6J mice (control, n = 6; HFD, n = 7) on genes involved in mitochondrial biogenesis and function and mtDNA copy number per nuclear DNA copy number. Data are shown as means ± SE and corrected for the expression of cyclophilin B for mRNA and glyceraldehyde-3-phosphate dehydrogenase for protein.

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  • TABLE 1

    Characteristics of the study population before the high-fat diet

    Age (years)23.0 ± 3.1
    Height (cm)179.7 ± 6.3
    Weight (kg)78.9 ± 13.2
    BMI (kg/m2)24.3 ± 3.0
    Vo2max (ml · kg−1 · min−1)48.8 ± 3.3
    Waist-to-hip ratio (AU)0.88 ± 0.1
    RQ–metabolic cart (AU)0.87 ± 0.1
    Fasting glucose (ml/dl)78.4 ± 4.7
    Fasting insulin (μl/ml)4.6 ± 1.4
    GDR (mg · kg FFM−1 · min−1)14.7 ± 4.1
    Free fatty acids (mmol)0.4 ± 0.1
    Body fat (%)16.2 ± 3.2
    Fat cell size (μl)0.93 ± 0.2
    • Data are means ± SD. GDR, glucose disposal rate; RQ, respiratory quotient.

  • TABLE 2

    Change in overnight fasting blood parameters after a 50% high-fat diet at energy balance and fixed activity level

    VariableBL1BL2HFD day 1HFD day 2HFD day 3
    Glucose (mg/dl)88.60 ± 7.3889.77 ± 8.7489.00 ± 9.7689.40 ± 7.2990.40 ± 9.03
    Insulin (mIU/ml)6.81 ± 3.026.98 ± 2.866.65 ± 3.006.07 ± 2.98*6.89 ± 2.67
    Free fatty acids (mmol)0.26 ± 0.080.28 ± 0.100.22 ± 0.080.25 ± 0.080.27 ± 0.10
    • Data are means ± SE. The HFD contained 50% fat. Repeated-measures ANOVA was used to test for time effects; P = 0.847, 0.130, and 0.047 for glucose, insulin, and free fatty acids, respectively.

    • *

      * Post hoc comparisons of each HFD day versus average of the two baseline (BL) values were significant (P < 0.05; Dunnett’s adjustment).

  • TABLE 3

    Microarray hits: oxidative phosphorylation

    GeneFold changeBaseline value (%)P
    NDUFB3↓ 1.471.4<0.01
    NDUFB5↓ 1.952.6<0.01
    SDHB↓ 2.441.6<0.01
    SLC25A12↓ 1.855.5<0.01
    NDUFV1↓ 1.952.6<0.01
    NDUFS1↓ 2.441.6<0.01
    • By microarray analysis, 297 genes were up- or downregulated after a HFD. Of those 297, 6 are known to be involved in oxidative phosphorylation or mitochondrial function. NDUFB3, NADH dehydrogenase (ubiquinone) 1β subcomplex, 3; NDUFB5, NADH dehydrogenase (ubiquinone) 1βsubcomplex, 5; NDUFV1, NADH dehydrogenase (ubiquinone) flavoprotein 1; NDUFS1, NADH dehydrogenase (ubiquinone) Fe-S protein 1; SDHB, succinate dehydrogenase complex, subunit B; SLC25A12, solute carrier family 25 (mitochondrial carrier).

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A High-Fat Diet Coordinately Downregulates Genes Required for Mitochondrial Oxidative Phosphorylation in Skeletal Muscle
Lauren M. Sparks, Hui Xie, Robert A. Koza, Randall Mynatt, Matthew W. Hulver, George A. Bray, Steven R. Smith
Diabetes Jul 2005, 54 (7) 1926-1933; DOI: 10.2337/diabetes.54.7.1926

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A High-Fat Diet Coordinately Downregulates Genes Required for Mitochondrial Oxidative Phosphorylation in Skeletal Muscle
Lauren M. Sparks, Hui Xie, Robert A. Koza, Randall Mynatt, Matthew W. Hulver, George A. Bray, Steven R. Smith
Diabetes Jul 2005, 54 (7) 1926-1933; DOI: 10.2337/diabetes.54.7.1926
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