title: Peroxisome proliferator-activated receptor-gamma coactivator-1alpha overexpression increases lipid oxidation in myocytes from extremely obese individuals.
abstract: OBJECTIVE
  To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha).
  
  
  METHODS
  FAO was studied in HSkMC from lean (BMI 22.4 +/- 0.9 kg/m(2); N = 12) and extremely obese (45.3 +/- 1.4 kg/m(2); N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1alpha expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete ((14)CO(2) production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis.
  
  
  RESULTS
  Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels. PGC-1alpha overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1alpha overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups.
  
  
  CONCLUSIONS
  Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance.
authors.affiliation: Department of Exercise and Sport Science, East Carolina University, Greenville, North Carolina, USA. consittl@ecu.edu
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Consitt
authors.forename: Jill A
authors.initials: JA
authors.lastname: Bell
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hulver
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Haynie
authors.forename: G Lynis
authors.initials: GL
authors.lastname: Dohm
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Houmard
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004272:DNA, Mitochondrial / Q000235:genetics / Q000302:isolation & purification; D005227:Fatty Acids / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008055:Lipids / Q000502:physiology*; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009767:Obesity, Morbid / Q000235:genetics*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010641:Phenotype; D013851:Thinness / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D005227:Fatty Acids; D006360:Heat-Shock Proteins; D008055:Lipids; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors