title: Mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy.
abstract: OBJECTIVE
  Lipid accumulation in skeletal muscle and the liver is strongly implicated in the development of insulin resistance and type 2 diabetes, but the mechanisms underpinning fat accrual in these sites remain incompletely understood. Accumulating evidence of muscle mitochondrial dysfunction in insulin-resistant states has fuelled the notion that primary defects in mitochondrial fat oxidation may be a contributory mechanism. The purpose of our study was to determine whether patients with congenital lipodystrophy, a disorder primarily affecting white adipose tissue, manifest impaired mitochondrial oxidative phosphorylation in skeletal muscle.
  
  
  METHODS
  Mitochondrial oxidative phosphorylation was assessed in quadriceps muscle using 31P-magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics after a standardized exercise bout in nondiabetic patients with congenital lipodystrophy and in age-, gender-, body mass index-, and fitness-matched controls.
  
  
  RESULTS
  The phosphocreatine recovery rate constant (k) was significantly lower in patients with congenital lipodystrophy than in healthy controls (P<0.001). This substantial (∼35%) defect in mitochondrial oxidative phosphorylation was not associated with significant changes in basal or sleeping metabolic rates.
  
  
  CONCLUSIONS
  Muscle mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy, a paradigmatic example of primary adipose tissue dysfunction. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could, at least in some circumstances, be a secondary consequence of adipose tissue failure. These data corroborate accumulating evidence that mitochondrial dysfunction can be a consequence of insulin-resistant states rather than a primary defect. Nevertheless, impaired mitochondrial fat oxidation is likely to accelerate ectopic fat accumulation and worsen insulin resistance.
authors.affiliation: Wolfson Brain Imaging Centre, Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Sleigh
authors.forename: Anna
authors.initials: A
authors.lastname: Stears
authors.forename: Kerrie
authors.initials: K
authors.lastname: Thackray
authors.forename: Laura
authors.initials: L
authors.lastname: Watson
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambineri
authors.forename: Sath
authors.initials: S
authors.lastname: Nag
authors.forename: V Irene
authors.initials: VI
authors.lastname: Campi
authors.forename: Nadia
authors.initials: N
authors.lastname: Schoenmakers
authors.forename: Soren
authors.initials: S
authors.lastname: Brage
authors.forename: T Adrian
authors.initials: TA
authors.lastname: Carpenter
authors.forename: Peter R
authors.initials: PR
authors.lastname: Murgatroyd
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Kemp
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D052497:Lipodystrophy, Congenital Generalized / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010725:Phosphocreatine / Q000378:metabolism; D052097:Quadriceps Muscle / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D001786:Blood Glucose; D010725:Phosphocreatine