Pharmacological Inhibition of Neutral Sphingomyelinase Attenuates Western Diet‐Induced Skeletal Muscle Insulin Resistance

ABSTRACT

Neutral sphingomyelinase (nSMase) hydrolyzes sphingomyelin to generate ceramide, a key bioactive lipid implicated in a number of pathological processes, including insulin resistance and diabetes. In this study, we investigate the role and mechanism of nSMase2 signaling in skeletal muscle lipid metabolic disorders and insulin resistance associated with Western diet (WD)‐induced obesity. Six‐week‐old C57BL/6J mice were fed either a WD enriched in saturated fat (46%) and fructose (17.5%) or a standard chow diet (CD) for 16 weeks. GW4869, an nSMase inhibitor, was administered intraperitoneally at a dose of 2.0 μg/g body weight every 48 h for 12 weeks. Sixteen weeks of WD feeding increased plasma nSMase activity and skeletal muscle nSMase2 expression that were associated with reduced insulin metabolic signaling in the phosphoinositide 3‐kinase/protein kinase B pathway, the development of glucose intolerance, and insulin resistance, all of which were blunted by GW4869 treatment. Concurrently, 16 weeks of WD feeding increased ceramide production and skeletal muscle CD36‐mediated signaling, which correlated with excessive lipid droplet accumulation and increased free fatty acid (FFA) levels in skeletal muscle ex vivo. These lipid metabolic disturbances were attenuated, in vivo, by treatment of mice with GW4869. Moreover, GW4869 inhibited WD‐induced pathological changes of skeletal muscle mitochondrial dysfunction, excessive oxidative stress, fibrosis and fiber type transition. These findings demonstrate that nSMase2 is involved in regulating CD36 signaling and may contribute to skeletal muscle FFA uptake, mitochondrial dysfunction, oxidative stress, fibrosis, and associated skeletal muscle insulin resistance in a mouse model of WD‐induced obesity.