The sphingolipid, ceramide, has a causal role in cardiometabolic disease. Ceramides containing saturated acyl tails of 16 and 18 carbons are considered particularly deleterious, due to their association with metabolic diseases and negative cardiovascular disease outcomes. There are six isoforms of the enzyme which catalyses ceramide production, ceramide synthase (CerS). Each isoform demonstrates specific fatty-acid substrate preference and tissue localisation. Selective pharmacological inhibition of CerS isoforms which produce deleterious ceramides, could potentially prevent cardiometabolic disease. Our study aims to characterise the anti-obesogenic effects of a novel CerS inhibitor, ET2.39, and its impact on metabolism.
HEK293 cells were treated with ET2.39 and the effects on ceramide levels and cell viability were evaluated. A 4-week high-fat diet (HFD) study was undertaken with male C57BL/6 mice provided Chow, HFD, or HFD + ET2.39 (~10 mg/kg/day) and physiological measurements (weight gain, fat and lean mass, glucose tolerance) taken throughout. Lipids extracted from cells and snap-frozen mouse tissues, were analysed via targeted LC-MS.
ET2.39 resulted in significantly reduced accumulation of C16:0 and C18:0 ceramides in HEK293 cells, without impacting cell viability. Dietary administration of ET2.39 prevented HFD-induced weight gain but not glucose intolerance. ET2.39 also slowed the accretion of fat mass and resulted in significantly decreased mass of epididymal fat in mice. Marked decreases in C18:0 ceramide levels in heart (20% lower) and quadriceps tissue (50% lower) were observed, with no major impact of ET2.39 on C16:0 ceramide levels in these tissues. Overall, the novel CerS inhibitor, ET2.39 demonstrates significant anti-obesogenic effects in mice provided HFD, in conjunction with limiting the accumulation of deleterious C18:0 ceramides in key metabolic tissues.