MON-688 Inhibition of sphingomyelinase attenuates Western diet-induced skeletal muscle insulin resistance

Abstract Disclosure: D. Chen: None. J. Habibi: None. L. Xie: None. G. Jia: None. Sphingomyelinases facilitate ceramide production and are essential for cell turnover, vesicle inward budding, and exosome release. Recent data suggest a distinct role for neutral sphingomyelinase (nSMase) in regulating ceramide-dependent exosome release and its connection to metabolic syndrome. We have recently demonstrated that elevated exosomal CD36 in endothelial cells is associated with increased skeletal muscle lipid disorders and insulin resistance. Here, we further investigated whether nSMase inhibition with GW4869, would attenuate Western diet (WD)-induced release of exosomal CD36, skeletal muscle lipid metabolic disorders and insulin resistance. Six week-old female C57BL/6L mice were fed either a WD containing excess fat (46%) and fructose (17.5%) for 16 weeks or a standard chow diet. Mice were variably treated with GW4869 (2.0 μg/g body weight, intraperitoneal injection every 48 h for 12 weeks). WD feeding increased nSMase2 expression and the plasma release of exosomal CD36, while causing glucose intolerance, HOMA-IR, and insulin resistance index, respectively. Moreover, these functional abnormalities were associated with reduced glucose transporter type 4 expression in conjunction with impaired insulin metabolic signaling in phosphoinositide 3-kinases/protein kinase B in skeletal muscle. GW4869 treatment prevented the WD-induced increases in in vivo glucose intolerance and tissue insulin resistance. GW4869 also inhibited WD-induced increases in the plasma release of exosomal CD36, skeletal muscle CD36 expression, lipid accumulation, oxidative stress, and mitochondrial dysfunction. These findings indicate that targeting nSMase prevents Western diet-induced increases in skeletal muscle lipid metabolic disorders and insulin resistance by attenuating the plasma release of exosomal CD36, skeletal muscle CD36 expression, and related tissue oxidative stress and mitochondria dysfunction. Presentation: Monday, July 14, 2025