Contribution of specific ceramides to obesity-associated metabolic diseases.

Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.