Sphingolipids:agents provocateurs in the pathogenesis of insulin resistance

Obesity is a major risk factor for a variety of chronic diseases, including diabetes mellitus, and comorbidities such as cardiovascular disorders. Despite recommended alterations in lifestyle, including physical activity and energy restriction, being the foundation of any anti-obesity therapy, this approach has so far proved to be of little success in tackling this major public health concern. Because of this, alternative means of tackling this problem are currently being investigated, including pharmacotherapeutic intervention. Consequently, much attention has been directed towards elucidating the molecular mechanisms underlying the development of insulin resistance. This review discusses some of these potential mechanisms, with particular focus on the involvement of the sphingolipid ceramide. Various factors associated with obesity, such as saturated fatty acids and inflammatory cytokines, promote the synthesis of ceramide and other intermediates. Furthermore, studies performed in cultured cells and in vivo associate these sphingolipids with impaired insulin action. In light of this, we provide an account of the research investigating how pharmacological inhibition or genetic manipulation of enzymes involved in regulating sphingolipid synthesis can attenuate the insulin-desensitising effects of these obesity-related factors. By doing so, we outline potential therapeutic targets that may prove useful in the treatment of metabolic disorders.