A Role for Ceramide, but Not Diacylglycerol, in the Antagonism of Insulin Signal Transduction by Saturated Fatty Acids*

By J. Chavez, Trina A. Knotts, Liping Wang, Guibin Li, R. Dobrowsky, G. Florant, S. Summers. Journal of Biological Chemistry, 2003

622 citations recorded by the source corpus.

Multiple studies suggest that lipid oversupply to skeletal muscle contributes to the development of insulin resistance, perhaps by promoting the accumulation of lipid metabolites capable of inhibiting signal transduction. Herein we demonstrate that exposing muscle cells to particular saturated free fatty acids (FFAs), but not mono-unsaturated FFAs, inhibits insulin stimulation of Akt/protein kinase B, a serine/threonine kinase that is a central mediator of insulin-stimulated anabolic metabolism. These saturated FFAs concomitantly induced the accumulation of ceramide and diacylglycerol, two products of fatty acyl-CoA that have been shown to accumulate in insulin-resistant tissues and to inhibit early steps in insulin signaling. Preventing de novo ceramide synthesis negated the antagonistic effect of saturated FFAs toward Akt/protein kinase B. Moreover, inducing ceramide buildup recapitulated and augmented the inhibitory effect of saturated FFAs. By contrast, diacylglycerol proved dispensable for these FFA effects. Collectively these results identify ceramide as a necessary and sufficient intermediate linking saturated fats to the inhibition of insulin signaling.

Subfields: Biochemistry, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/530e354093d86e565260c2908ce1717770206b7e

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Citations in the corpus

Central leptin regulates total ceramide content and sterol regulatory element binding protein-1C proteolytic maturation in rat white adipose tissue. (2009, background): “is sufficient to elicit effects on insulin signaling (45, 46).”
Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease. (2010, background): “However, intramuscular triacylglycerol depots are an indirect marker of insulin resistance, since the more soluble lipid metabolites such as ceramides, diacylglycerols, and long-chain fatty acyl-CoAs interfere with the postreceptor insulin signaling cascade (77, 78, 90, 193, 194, 410, 421).”
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A ceramide-centric view of insulin resistance. (2012, background): “In all cell types tested, however, ceramide blocks activation of Akt/PKB (Chavez et al., 2003; Powell et al., 2003; Salinas et al., 2000; Stratford et al., 2001; Stratford et al., 2004; Teruel et al., 2001; Zinda et al., 2001).”
Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. (2007, methodology): “Phosphorylation of Akt/PKB was assessed by western blot using phosphospecific antibodies recognizing the activating serine 473 site.”
Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. (2004, background): “Lastly, increased muscle ceramide levels (secondary to increased long chain FA-CoAs) interfere with glucose transport and inhibit glycogen synthase in muscle via activation of protein kinase B (88, 89) (Fig.”
Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. (2004, background): “Recent studies have confirmed the role of ceramide in inhibition of Akt and downstream signaling, but not IRS-1 function, in 3T3-L1 adipocytes (33) or L6 muscle cells (34).”
Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. (2011, background): “Moreover, GCS inhibitors exacerbated palmitate antagonism of Akt/PKB in myocytes, coinciding with their enhancement of ceramide production (43).”