Myostatin Knockout Mice Are Protected from High-Fat Diet Induced Obesity and Insulin Resistance.

Choi, Cheol Soo; Distefano, Alberto; Kim, Sheene; Kulkarni, Ameya; Hwang, Yu-Jin; Cline, Gary; Shulman, Gerald

Myostatin is a negative regulator of skeletal muscle mass and myostatin null mice have been shown to have a twofold increase in muscle mass. To assess the impact of myostatin deficiency on fat and glucose metabolism in vivo, body weight, fat mass, energy expenditure (EE), and lipid profile were measured in myostatin -/- mice (KO) and wild type (WT) mice. In addition, insulin action was examined during a 2-hour hyperinsulinemic (3.0mU/Kg/min)-euglycemic clamp in myostatin KO and WT mice. Body weight in myostatin KO mice was higher than that of WT (32.9±0.1 vs. 26.3±0.4 g, P<0.0001), which could entirely be attributed to increased lean body mass (27.7±0.2 vs. 20.2±0.3 g, P<0.001). Myostatin KO mice were resistant to high-fat diet induced obesity (fat mass change in KO vs. WT: 3.64±0.34 vs. 5.17±0.54 g, P=0.03) and hyperlipidemia (cholesterol in KO vs. WT: 58.6±5.1 vs. 100.3±6.1 mg/dl, P<0.0001, triglyceride in KO vs. WT: 48.0±1.7 vs. 86.3±7.8 mg/dl P<0.0001). Surprisingly, energy expenditure in KO mice was significantly lower in the KO mice than WT mice (13.6±0.3 vs. 15.0±0.4 kcal/Kg/h, P=0.02) although there were no differences in energy intake or activity. In addition, insulin sensitivity was markedly increased in myostatin KO mice fed regular chow, as reflected by 70% higher steady-state glucose infusion rates (KO vs. WT: 71.8±5.0 vs. 40.5±3.9 mg/kg/min, P=0.001) during the clamp. This increase in insulin responsiveness could be accounted for by a 90% increase in insulin-induced suppression of hepatic glucose production (KO vs. WT: 1.1±1.4 vs. 10.2±2.4 mg/kg/min, P<0.001) and a 44% increase in insulin stimulated whole body glucose uptake (KO vs. WT: 72.9±4.4 vs. 50.6±2.5 mg/kg/min, P<0.001). Insulin-stimulated glycogen synthesis of myostatin KO was also increased by 100%. Similar increases in insulin stimulated suppression of hepatic glucose production (KO vs. WT: 3.6±4-1.4 vs. 13.8±2.3 mg/kg/min, P<0.01) and peripheral glucose uptake (KO vs. WT: 46.7±3.6 vs. 35.6±l.5 mg/kg/min, P<0.01) were observed in myostatin KO mice fed a high fat diet. CONCLUSION: These data demonstrate that myostatin KO mice are insulin sensitive and protected against high fat diet induced obesity and insulin resistance. These data suggest that myostatin is an excellent therapeutic target for treatment of obesity and insulin resistance associated with type 2 diabetes mellitus.

LABORATORY mice; DIET; OBESITY; INSULIN resistance; BODY weight

Diabetes, 2007, Vol 56, pA84

0012-1797

Academic Journal