A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids.
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.
Chavez
Jose Antonio
JA
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins 80523-1870, USA.
Knotts
Trina A
TA
Wang
Li-Ping
LP
Li
Guibin
G
Dobrowsky
Rick T
RT
Florant
Gregory L
GL
Summers
Scott A
SA
D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis / Q000502:physiology*; D004075:Diglycerides / Q000502:physiology*; D005227:Fatty Acids / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects*
D002518:Ceramides; D004075:Diglycerides; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D011518:Proto-Oncogene Proteins; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3