Sphingolipids and insulin resistance: the five Ws

Inhibition of sphingolipid synthesis increases insulin sensitivity, resolves hepatic steatosis, and prevents the onset of diabetes in obese rodents. I herein review these interventional studies, aiming to summarize the five Ws - the 'Who, What, Where, When, and Why' questions that need to be addressed to understand roles of sphingolipids in the pathogenesis of diabetes.

Who: ceramides and glucosylceramides are likely to be independent antagonists of insulin action. Where: recent data suggest that ceramides may inhibit insulin action in skeletal muscle, whereas glucosylceramides may be more efficacious in adipose tissue. In contrast, sphingolipid accumulation in the liver appears to be insufficient to induce insulin resistance. What: ceramides and glucosylceramides inhibit different insulin signaling events, but it is unclear whether these actions account for the broad spectrum of therapeutic benefits resulting from sphingolipid depletion. When: recent data suggest that obesity-induced inflammation is important for the induction of sphingolipid synthesis. Why: sphingolipids have an evolutionarily conserved role to starve cells of nutrients, and the inhibition of insulin action is possibly a component of this broader action.

Despite considerable attention to the question of how sphingolipids induce metabolic disease, there exist enormous gaps in knowledge. Further elucidation of these molecular details will be essential for the development of new therapeutic strategies for inhibiting sphingolipid action and ameliorating metabolic diseases.