Skeletal muscle inflammation and insulin resistance in obesity

Introduction Obesity is becoming a global epidemic, increasing the health burden of associated complications of insulin resistance and diseases such as cardiovascular disease (1). Because insulin resistance leads to type 2 diabetes (T2D) (2), T2D incidence and prevalence are also increasing rapidly. The number of adults with diagnosed diabetes in the United States nearly quadrupled over 32 years, from 5.5 million in 1980 to 21.3 million in 2012; 90% to 95% of these individuals have T2D (3). Molecular links between obesity and insulin resistance and T2D remain incompletely understood but may include chronic inflammation, particularly in adipose tissue (AT) (4–8). AT inflammation may contribute to whole-body insulin resistance and T2D via the endocrine effects of inflammatory molecules secreted by AT (known as adipokines) on insulin sensitivity in various tissues, particularly skeletal muscle (SM) and liver. Additionally, dysregulation of preadipocyte/adipocyte functions accelerates fat spillover from AT to SM and liver, resulting in ectopic fat deposition and insulin resistance in these tissues, which contribute to systemic insulin resistance and T2D (5, 7, 9–13). SM is the most important organ for whole-body glucose homeostasis (14, 15) and is responsible for approximately 80% of insulin-stimulated whole-body glucose uptake and disposal under normal conditions (15–18). Insulin resistance in SM is the major defect in T2D (16–18) and is therefore central to systemic insulin resistance and T2D. While studies have focused on the roles of intramyocellular lipids, mitochondrial defects, and endocrine effects of adipokines on SM insulin resistance (10, 12, 15), emerging evidence indicates that inflammation also occurs in SM in the setting of obesity and may exert autocrine or paracrine effects on myocyte metabolic functions. In this Review we focus on obesity-linked SM inflammation and its roles in muscle insulin resistance.