Sphingosine Kinase 1 is regulated by PPARα in response to free fatty acids and mediates skeletal muscle IL‐6 production and signaling in diet‐induced obesity

Abstract

Plasma fatty acids increase in obesity and diabetes; subsequent lipid overload to cells and tissues mediates numerous pathological processes. This is due in part to aberrant synthesis of bioactive lipids. We previously demonstrated that palmitate (PAL) increased sphingosine‐1‐phosphate through regulation of sphingosine kinase 1 (SphK1); however, potential functions and in vivo relevance of this have not been addressed. Data demonstrate that PAL mediated SphK1 induction through PPARα. Moreover, PAL treatment induced IL‐6 in a SphK1‐dependent manner, which was attenuated by inhibition of sphingosine‐1‐phosphate receptor 3 (S1PR3). Diet‐induced obesity in mice demonstrated a requirement for SphK1 for IL‐6 expression in muscle and plasma. Moreover, muscle IL‐6 signaling was activated in wild type but not SphK1‐/‐ mice. These data indicate that PPARα regulates SphK1 expression in fatty acid oversupply and links PAL to muscle IL‐6 production. Moreover, the activation of muscle IL‐6 signaling in diet‐induced obesity suggests a potential role for SphK1 in obesity‐associated pathology. This work was supported by a VA Merit award and a COBRE award (NIH P20 RR017677) to LAC and a GAANN fellowship in Lipidomics and Systems Biology to JSR.