Endocrine Abstracts

Excess consumption of saturated fatty acids may lead to an increased production of ceramides that contribute to development of insulin resistance and type 2 diabetes. Substantial research demonstrated that inhibition of ceramide biosynthesis ameliorates atherosclerosis, hepatic steatosis, insulin resistance and obesity. However, as ceramides and their sphingolipid products are involved in multiple fundamental cellular processes, concerns exist about possible risks or adverse effects resulting from overall inhibition of sphingolipid synthesis for treatment of chronic diseases. Therefore, the inhibition of specific ceramide species represents a new strategy for pharmaceutical intervention. Recent research demonstrated that specifically CerS6 mediated C16 ceramide synthesis plays a key role in the development of obesity mediated insulin resistance.

In the current study, we investigated the effects of specifically knocking-down CerS6 in ob/ob mice using CerS6 anti-sense oligonucleotides (ASO). In this animal model, CerS6 expression is significantly higher vs. lean control mice (~2 fold in the liver and BAT) which correlates with a 4-fold increase of C16 ceramide in the plasma and a 2-fold increase in the liver. CerS6 ASO treatment led to selective and significant ~80% knockdown of the CerS6 expression in the liver and correlated with a significant 50% reduction of C16 ceramide in the liver and plasma compared to control ASO-treated ob/ob mice. CerS6 knockdown protected against body weight gain and was associated with a significant reduction in fat mass and blood glucose levels. Moreover, insulin resistance was significantly improved by ASO treatment as evidenced by oral glucose tolerance and insulin tolerance tests (~50% reduction in AUC during oGTT).

In conclusion, CerS6 dependent C16 ceramide synthesis represents a distinct sphingolipid species, which contributes to the development of obesity and insulin resistance and therefore may represent a unique and attractive novel target to treat obesity and type 2 diabetes.