Role of nSMase in diet-induced skeletal muscle insulin resistance

Neutral sphingomyelinase (nSMase) hydrolyze sphingomyelin to generate ceramide, a key bioactive lipid known to pathological diseases, including insulin resistance and diabetes. In this study, we further examined the role of nSMase signaling in contributing to lipid metabolic disorders, skeletal muscle insulin resistance, and their underlying molecular mechanisms in diet-induced obesity. Six week-old of C57BL/6L mice were fed with a Western diet (WD) containing excess fat (46%) and fructose (17.5%) or a standard chow diet (CD) for 16 weeks. Mice were treated with GW4869 (2.0 μg/g body weight) by intraperitoneal injection every 48 hours for 12 weeks. Sixteen weeks of WD feeding increased plasma nSMase activity and expression, leading to the development of glucose intolerance and skeletal muscle insulin resistance that were blunted in in vivo GW4869 treatment. Improved insulin sensitivity in GW4869 treated mice was characterized by increased insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B pathways. Meanwhile, 16 weeks of WD feeding also increased ceramide production and skeletal muscle CD36 signaling that were related to ex vivo excessive skeletal muscle lipid droplet accumulation and increased free fatty acid (FFA) levels. These lipid metabolic disorders were blunted in vivo GW4869 treated mice. Moreover, inhibition of nSMase with GW4869 also inhibited 16 weeks of WD-induced pathological alterations of skeletal muscle in mitochondrial dysfunction, excessive oxidative stress, fibrosis, fiber type transition. These findings demonstrate that nSMase participates in regulating CD36 signaling, skeletal muscle FFA uptake, mitochondrial dysfunction, oxidative stress, fibrosis, and associated skeletal muscle insulin resistance in diet-induced obesity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.