Ceramides and glucosylceramides are independent antagonists of insulin signaling.

Inhibitors of sphingolipid synthesis protect mice from diet induced-insulin resistance, and sphingolipids such as ceramides and glucosylated-ceramides (e.g., GM3) are putative nutritional intermediates linking obesity to diabetes risk. Herein we investigated the role of each of these sphingolipids in muscle and adipose tissue and conclude that they are independent and separable antagonists of insulin signaling. Of particular note, ceramides antagonize insulin signaling in both myotubes and adipocytes, whereas glucosyceramides are only efficacious in adipocytes: 1) In myotubes exposed to saturated fats, inhibitors of enzymes required for ceramide synthesis enhance insulin signaling, but those targeting glucosylceramide synthase have no effect. 2) Exogenous ceramides antagonize insulin signaling in myotubes, whereas ganglioside precursors do not. 3) Overexpression of glucosylceramide synthase in myotubes induces glucosylceramide but enhances insulin signaling. In contrast, glucosylated ceramides have profound effects in adipocytes. For example, either ganglioside addition or human glucosylceramide synthase overexpression suppresses insulin signaling in adipocytes. These data have important mechanistic implications for understanding how these sphingolipids contribute to energy sensing and the disruption of anabolism under conditions of nutrient oversupply.