Targeting the homeodomain of ceramide-synthase can ameliorate insulin resistance

Multiple studies have linked ceramide accumulation with insulin resistance and diabetes. Ceramide Synthases (CerS) are at the center of ceramide de novo formation. Impaired CerS activity leads to lower ceramide and resolves insulin resistance. Drosophila has only one CerS, named Schlank, which contains a catalytic lag1p motif and, like many CerS, a homeodomain regulating lipid homeostasis. How CerS homeodomains are associated with diabetes has been little studied. Here we demonstrate that, depending on the respective mutation in the CerS homeodomain high sugar diet (HSD)-induced insulin resistance is exacerbated or ameliorated. HSD shifts the profile of sphingolipids towards polyunsaturated longer sphingoid bases, systemic insulin signaling is reduced, as indicated by nuclear accumulation of FoxO, and secretion of insulin-like peptide 2 (DILP2) is impaired. Expression of a CerS variant with a mutation in the nuclear localization signal 2 within its homeodomain in the fat body improves systemic insulin signaling and DILP2 release. Thus, the CerS homeodomain may be a potential target to attenuate insulin resistance.