SUN-692 - Nsmase Participates in Western Diet-Induced Vascular Insulin Resistance

Neutral sphingomyelinase (nSMase) hydrolyze sphingomyelin to generate ceramide, leading to insulin resistance and diabetes. In this study, we further examined the role of nSMase signaling in contributing to vascular lipid metabolic disorders, insulin resistance, as well as their underlying molecular mechanisms in Western 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 ?g/g body weight) by intraperitoneal injection every 48 hours for 12 weeks. 16 weeks of WD feeding increased plasma nSMase activity, in vivo glucose intolerance and vascular insulin resistance, accompanied by attenuated activation of AMPK and endothelial nitric oxide synthase in aorta. These effects were blunted by in vivo GW4869 treatment. Meanwhile, these metabolic abnormalities were accompanied by aortic stiffening and impaired vasorelaxation, as determined by pulse wave velocity (PWV) and wire myography, respectively. However, GW4869 also inhibited WD-induced aortic CD36 expression, FFA uptake, excessive lipid accumulation, oxidative stress, inflammatory responses, and aortic remodeling. These findings indicate that nSMase participates in regulating CD36 signaling, vascular FFA uptake, fibrosis, stiffening and associated vascular insulin resistance in diet-induced obesity.

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