A LOSS-OF-FUNCTION MUTATION IN MYOSTATIN REDUCES TNF_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 (Mstn^Ln) in either one or both alleles of the Mstn gene shows how Mstn deficiency protects whole-body insulin sensitivity.

Research Design and Methods. Mstn^Ln/Ln mice were weaned onto high-fat diet (HFD) or chow. HFD-fed Mstn^Ln/Ln mice exhibited high lean, low fat, body compositions compared to wild types. Wild type and heterozygous and homozygous mutant mice were bled to determine basal levels of insulin, glucose, and HOMA-IR (insulin resistance). To evaluate postprandial insulin sensitivity between animals of a similar size, GTT, ITT, and hyperinsulinemic-euglycemic clamp studies were performed with heterozygous and homozygous mutant mice. Quantitative RT-PCR (qPCR) 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 to heterozygous mice. Hyperinsulinemic-euglycemic clamp studies revealed a dramatically improved glucose infusion rate (GINF), glucose disposal rate (GDR), and hepatic glucose production (HGP) in 11 month old Mstn^Ln/Ln mice on HFD. Improvements to muscle and liver insulin sensitivity (∼200 to 400%) correlated with 50 to 75% decreased TNF_α production and coincided with severe Mstn deficiency. Hepatosteatosis appeared to be ameliorated. Short term treatment of Mstn^Ln/Ln mice with recombinant Mstn led to increased plasma TNF_α and insulin resistance.

Conclusion. We find severe Mstn deficiency caused by Ln mutations in HFD-fed mice protect muscle and liver against obesity-induced insulin resistance.