Acid ceramidase overexpression prevents the inhibitory effects of saturated fatty acids on insulin signaling.
Recent studies indicate that insulin resistance and type 2 diabetes result from the accumulation of lipids in tissues not suited for fat storage, such as skeletal muscle and the liver. To elucidate the mechanisms linking exogenous fats to the inhibition of insulin action, we evaluated the effects of free fatty acids (FFAs) on insulin signal transduction in cultured C2C12 myotubes. As we described previously (Chavez, J. A., and Summers, S. A. (2003) Arch. Biochem. Biophys. 419, 101-109), long-chain saturated FFAs inhibited insulin stimulation of Akt/protein kinase B, a central regulator of glucose uptake and anabolic metabolism. Moreover, these FFAs stimulated the de novo synthesis of ceramide and sphingosine, two sphingolipids shown previously to inhibit insulin action. To determine the contribution of either sphingolipid in FFA-dependent inhibition of insulin action, we generated C2C12 myotubes that constitutively overexpress acid ceramidase (AC), an enzyme that catalyzes the lysosomal conversion of ceramide to sphingosine. AC overexpression negated the inhibitory effects of saturated FFAs on insulin signaling while blocking their stimulation of ceramide accumulation. By contrast, AC overexpression stimulated the accrual of sphingosine. These results support a role for aberrant accumulation of ceramide, but not sphingosine, in the inhibition of muscle insulin sensitivity by exogenous FFAs.
Chavez
Jose Antonio
JA
Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, 84132, USA.
Holland
William L
WL
Bär
Julia
J
Sandhoff
Konrad
K
Summers
Scott A
SA
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D002517:Galactosylgalactosylglucosylceramidase / Q000235:genetics* / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000378:metabolism
D018076:DNA, Complementary; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D019308:Palmitic Acid; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D002517:Galactosylgalactosylglucosylceramidase; D013110:Sphingosine