title: Overfeeding reduces insulin sensitivity and increases oxidative stress, without altering markers of mitochondrial content and function in humans.
abstract: BACKGROUND
  Mitochondrial dysfunction and increased oxidative stress are associated with obesity and type 2 diabetes. High fat feeding induces insulin resistance and increases skeletal muscle oxidative stress in rodents, but there is controversy as to whether skeletal muscle mitochondrial biogenesis and function is altered.
  
  
  RESULTS
  Forty (37 ± 2 y) non-obese (25.6 ± 0.6 kg/m(2)) sedentary men (n = 20) and women (n = 20) were overfed (+1040 ± 100 kcal/day, 46 ± 1% of energy from fat) for 28 days. Hyperinsulinemic-euglycemic clamps were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28 of overfeeding in a sub cohort of 26 individuals (13 men and 13 women) that consented to having all 3 biopsies performed. Weight increased on average in the whole cohort by 0.6 ± 0.1 and 2.7 ± 0.3 kg at days 3 and 28, respectively (P<0.0001, without a significant difference in the response between men and women (P = 0.4). Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8 ± 2.8 at baseline to 50.3 ± 2.5 µmol/min/kg FFM at day 28 of overfeeding (P = 0.03) without a significant difference between men and women (P = 0.4). Skeletal muscle protein carbonyls and urinary F2-isoprostanes increased with overfeeding (P<0.05). Protein levels of muscle peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and subunits from complex I, II and V of the electron transport chain were increased at day 3 (all P<0.05) and returned to basal levels at day 28. No changes were detected in muscle citrate synthase activity or ex vivo CO(2) production at either time point.
  
  
  CONCLUSIONS
  Peripheral insulin resistance was induced by overfeeding, without reducing any of the markers of mitochondrial content that were examined. Oxidative stress was however increased, and may have contributed to the reduction in insulin sensitivity observed.
authors.affiliation: Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Dorit
authors.initials: D
authors.lastname: Samocha-Bonet
authors.forename: Lesley V
authors.initials: LV
authors.lastname: Campbell
authors.forename: Trevor A
authors.initials: TA
authors.lastname: Mori
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Croft
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Greenfield
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.forename: Leonie K
authors.initials: LK
authors.lastname: Heilbronn
mesh_terms: D000328:Adult; D001706:Biopsy; D001786:Blood Glucose; D001835:Body Weight; D002950:Citrate (si)-Synthase / Q000378:metabolism; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D059305:Diet, High-Fat; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D015430:Weight Gain / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C116431:src kinase associated phosphoprotein 2; D002950:Citrate (si)-Synthase