Effect of Weight Loss on Insulin Sensitivity and Intramuscular Long-Chain Fatty Acyl-CoAs in Morbidly Obese Subjects

Effect of Weight Loss on Insulin Sensitivity and Intramuscular Long-Chain Fatty Acyl-CoAs in Morbidly Obese Subjects Joseph A. Houmard 1 , Charles J. Tanner 1 , Chunli Yu 2 , Paul G. Cunningham 1 , Walter J. Pories 1 , Kenneth G. MacDonald 1 and Gerald I. Shulman 2 1 Departments of Exercise and Sport Science, Surgery, and the Human Performance Laboratory and Diabetes/Obesity Center, East Carolina University, Greenville, North Carolina 2 Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut Abstract Increases in intramyocellular long-chain fatty acyl-CoAs (LCACoA) have been implicated in the pathogenesis of insulin resistance in skeletal muscle. To test this hypothesis, we measured muscle (vastus lateralis) LCACoA content and insulin action in morbidly obese patients ( n = 11) before and after weight loss (gastric bypass surgery). The intervention produced significant weight loss (142.3 ± 6.8 vs. 79.6 ± 4.1 kg for before versus after surgery, respectively). Fasting insulin decreased by ∼ 84% (23.3 ± 3.8 vs. 3.8 ± 0.5 mU/ml), and insulin sensitivity, as determined by minimal model, increased by ∼360% (1.2 ± 0.3 vs. 4.1 ± 0.5 min −1 · [μ U/kg −1 ]) indicating enhanced insulin action. Muscle palmityl CoA (16:0; 0.54 ± 0.08 vs. 0.35 ± 0.04 nmol/g wet wt) concentration decreased by ∼35% ( P < 0.05) with weight loss, whereas stearate CoA (18:0; −17%; 0.65 ± 0.05 vs. 0.54 ± 0.03 nmol/g wet wt) and linoleate CoA (18:2; −30%; 2.47 ± 0.27 vs. 1.66 ± 0.19 nmol/g wet wt) were also reduced ( P < 0.05). There were no statistically significant declines in muscle palmitoleate CoA (16:1), oleate CoA (18:1), or total LCACoA content. These data suggest that a reduction in intramuscular LCACoA content may be responsible, at least in part, for the enhanced insulin action observed with weight loss in obese individuals. Footnotes Address correspondence and reprint requests to Joseph A. Houmard, Human Performance Laboratory, Room 371, Ward Sports Medicine Building, East Carolina University, Greenville, NC 27858. E-mail: houmardj{at}mail.ecu.edu . Received for publication 7 February 2002 and accepted in revised form 5 June 2002. HOMA, homeostasis model assessment; LCACoA, long-chain fatty acyl-CoA; S I , sensitivity index. DIABETES