title: Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1β involves reductions in long-chain acyl-CoA levels and oxidative stress.
abstract: OBJECTIVE
  To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1β [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance.
  
  
  METHODS
  Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1β in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1β on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp.
  
  
  RESULTS
  Pgc-1β gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1β. In rats fed a HFD, increasing the levels of Pgc-1β partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences.
  
  
  CONCLUSIONS
  Our data show that an increase in Pgc-1β expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.
authors.affiliation: Diabetes & Obesity Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: L E
authors.initials: LE
authors.lastname: Wright
authors.forename: A E
authors.initials: AE
authors.lastname: Brandon
authors.forename: A J
authors.initials: AJ
authors.lastname: Hoy
authors.forename: G-B
authors.initials: GB
authors.lastname: Forsberg
authors.forename: C J
authors.initials: CJ
authors.lastname: Lelliott
authors.forename: J
authors.initials: J
authors.lastname: Reznick
authors.forename: L
authors.initials: L
authors.lastname: Löfgren
authors.forename: J
authors.initials: J
authors.lastname: Oscarsson
authors.forename: M
authors.initials: M
authors.lastname: Strömstedt
authors.forename: G J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: N
authors.initials: N
authors.lastname: Turner
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects; D007333:Insulin Resistance / Q000502:physiology*; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D008931:Mitochondria, Muscle / Q000502:physiology; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D004041:Dietary Fats; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors