The role of ceramides in metabolic disorders: when size and localization matters

Ceramide accumulation is a hallmark in the manifestation of numerous obesity-related diseases, such as type 2 diabetes mellitus and atherosclerosis. Until the early 2000s, ceramides were viewed as a homogenous class of sphingolipids. However, it has now become clear that ceramides exert fundamentally different effects depending on the specific fatty acyl chain lengths, which are integrated into ceramides by a group of enzymes known as dihydroceramide synthases. In addition, alterations in ceramide synthesis, trafficking and metabolism in specific cellular compartments exert distinct consequences on metabolic homeostasis. Here, we examine the emerging concept of how the intracellular localization of ceramides with distinct acyl chain lengths can regulate glucose metabolism, thus emphasizing their potential as targets in the development of novel and specific therapies for obesity and obesity-associated diseases. This Review examines the emerging concept that distinct ceramide species in specific cellular compartments can exert specialized functions in obesity-associated deterioration of metabolic homeostasis. Ceramides are therefore potential targets in the development of novel and specific therapies for obesity and obesity-associated diseases. Key points Increased levels of ceramides during obesity contribute to cellular dysfunction in key metabolic tissues, which results in insulin resistance. The synthesis of ceramides with varying acyl chain lengths is regulated by six ceramide synthases (CerS1–CerS6), and their expression profiles differ throughout the body. Genetic manipulation of individual ceramide synthases has identified a highly regulated specificity of distinct acyl chain ceramides in the pathogenesis of obesity, type 2 diabetes mellitus, hepatocellular carcinoma, myelination, hair loss and skin barrier function. The location of ceramides with different acyl chains is important for cellular function and could contribute to metabolic tissue function. Targeting ceramides with different acyl chains within different intracellular locations could help to provide new therapeutics for a range of obesity-related diseases.