Activation of toll‐like receptor‐4 modulates skeletal muscle substrate metabolism in a manner that mimics the metabolic phenotype observed in skeletal muscle of obese humans

Abstract

Obesity is associated with chronic inflammation and the development of type 2 diabetes. Skeletal muscle from obese humans is resistant to insulin and characterized by abnormal substrate metabolism, i.e. increased glycolytic activity, reduced oxidative capacity, and elevated lipid accumulation. Toll‐like receptors (TLRs) are transmembrane receptors that are important in the induction of inflammatory responses. TLRs have been linked to lipid‐induced skeletal muscle insulin resistance and may contribute to reduced oxidative capacity and skeletal muscle lipid accumulation associated with obesity. In the current study, we demonstrate that the TLR4 signaling pathway is up regulated in skeletal muscle of obese humans and regulates substrate metabolism in a manner that reproduces the metabolic phenotype of skeletal muscle observed with obesity. TLR4 gene expression is increased in skeletal muscle of obese humans (p<0.001) and significantly related to BMI (r=0.92, p<0.001) and intramyocellular triglyceride synthesis (r=0.86, p<0.006). In addition, treatment of skeletal muscle cells with Lipopolysaccharide results in a 15% reduction in fatty acid oxidation (p<0.002), a 30% increase in glucose oxidation (p=0.04), and a 33% increase in triglyceride synthesis (p<0.002). These results provide a potential mechanism linking innate immunity with abnormal substrate metabolism associated with obesity.Supported by the American Diabetes Association (Junior Faculty Award, MWH) and the National Institutes of Health (DK078765‐01, MWH).