C16:0-ceramide signals insulin resistance

Abstract

A substantive literature has accumulated implicating sphingolipids, in particular ceramides, as mediators of insulin resistance in metabolic syndrome. Thanks to recent technical advances in mouse genetics and lipidomics, two independent laboratories identify the same sphingolipid, C16:0-ceramide, as principal mediator of obesity-related insulin resistance (Turpin et al., 2014; Raichur et al., 2014).

Figure 1. Impact of High-Fat Diet-Induced C16:0-Ceramide on Metabolic Dysregulation

Sphingolipid synthesis begins with condensation of palmitoyl-CoA with serine forming 3-ketosphinganine, which is reduced to dihydrosphingosine (a.k.a. sphinganine) and thereafter acylated to dihydroceramide. Further reduction of the sphingoid base sphinganine backbone by formation of a trans-double bond yields ceramide, a central molecule in sphingolipid metabolism. Transfer of a phosphocholine headgroup from phosphatidylcholine to ceramide yields sphingomyelin, the most abundant mammalian sphingolipid, concentrated in the external plasma membrane, while glycosylation in Golgi begins the formation of a plethora of glycosphingolipids with complex carbohydrate headgroups. Alternately, ceramide deacylation by ceramidase frees up sphingosine for compartmentalized phosphorylation yielding sphingosine 1-phosphate. In the context of insulin resistance, high-fat diet selectively upregulates expression of CerS6, the C16:0-ceramide synthetic enzyme, and concomitantly provides increased amounts of the CerS6 substrate palmitate, enhancing C16:0-ceramide production. C16:0-ceramide induces insulin resistance by antagonizing insulin receptor (IR)-stimulated PI3K/Akt signaling, which attenuates glucose metabolism. In addition, Akt normally stimulates lipid metabolism by SREBP-dependent mechanisms, which would presumably be inhibited, although not directly investigated in the current manuscripts. C16:0-ceramide also appears to directly inhibit mitochondrial electron transport, by an as-yet-unknown mechanism, thereby indirectly suppressing β-oxidation. Inhibition of β-oxidation reduces fatty acid disposal, promoting accumulation of excessive TG in lipid droplets.