Loss-of-Function Mutation in Myostatin Reduces Tumor Necrosis Factor α Production and Protects Liver Against Obesity-Induced Insulin Resistance

Abstract

OBJECTIVE: Insulin resistance develops in tandem with obesity. Ablating myostatin (Mstn) prevents obesity, so we investigated if Mstn deficiency could improve insulin sensitivity. A loss-of-function mutation (MstnLn) in either one or both alleles of the Mstn gene shows how Mstn deficiency protects whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS: MstnLn/Ln mice were weaned onto a high-fat diet (HFD) or standard diet. HFD-fed MstnLn/Ln mice exhibited high lean, low-fat body compositions compared with wild types. Wild-type and heterozygous and homozygous mutant mice were bled to determine basal levels of insulin, glucose, and homeostasis model assessment of insulin resistance. To evaluate postprandial insulin sensitivity between animals of a similar size, glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamp studies were performed with heterozygous and homozygous mutant mice. Quantitative RT-PCR quantified TNF∝, IL-6, IL-1β, F4/80, GPR43, and CD36 expression in muscle, fat, and liver. Histological analysis measured hepatosteatosis. RESULTS: Homozygous mutants were glucose tolerant and protected against overall insulin resistance compared with heterozygous mice. Hyperinsulinemic-euglycemic clamp studies revealed a dramatically improved glucose infusion rate, glucose disposal rate, and hepatic glucose production in 11-month-old MstnLn/Ln mice on an HFD. Improvements to muscle and liver insulin sensitivity (∼200–400%) correlated with 50–75% decreased tumor necrosis factor (TNF)α production and coincided with severe Mstn deficiency. Hepatosteatosis appeared to be ameliorated. Short-term treatment of MstnLn/Ln mice with recombinant Mstn led to increased plasma TNFα and insulin resistance. CONCLUSIONS: We find that severe Mstn deficiency caused by Ln (lean) mutations in HFD-fed mice protects muscle and liver against obesity-induced insulin resistance.