Mitochondrial Oxidative Phosphorylation Is Impaired in Patients with Congenital Lipodystrophy

• Published in: The journal of clinical endocrinology and metabolism Vol. 97; no. 3; pp. E438 - E442
• Main Authors: Sleigh, Alison, Stears, Anna, Thackray, Kerrie, Watson, Laura, Gambineri, Alessandra, Nag, Sath, Campi, V. Irene, Schoenmakers, Nadia, Brage, Soren, Carpenter, T. Adrian, Murgatroyd, Peter R, O'Rahilly, Stephen, Kemp, Graham J, Savage, David B
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-03-2012; Copyright by The Endocrine Society
• Subjects: Adult; Blood Glucose - metabolism; Female; Humans; Insulin Resistance - physiology; JCEM Online: Brief Reports; Lipodystrophy, Congenital Generalized - metabolism; Lipodystrophy, Congenital Generalized - physiopathology; Male; Mitochondria, Muscle - metabolism; Oxidative Phosphorylation; Phosphocreatine - metabolism; Quadriceps Muscle - metabolism; Quadriceps Muscle - physiopathology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2011-2587

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.
Research Design and 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.