Stearoyl-CoA desaturase and insulin signaling--what is the molecular switch?
Increasing evidence suggests that stearoyl-CoA desaturase (SCD), the rate-limiting enzyme of monounsaturated fatty acid biosynthesis, is an important factor in the pathogenesis of lipid-induced insulin resistance. Mice with a targeted disruption of the SCD1 gene have improved glucose tolerance compared to wild-type mice, despite lower fasting plasma insulin levels. Increased SCD activity has been found in insulin-resistant humans and animals, whereas SCD1 deficiency attenuates both diet- and genetically-induced impairment of insulin action. Phosphorylation of serine and threonine residues on insulin receptor, insulin receptor substrates (IRS1 and IRS2), and on Akt has been shown to be the major step in insulin signaling that is altered due to the lack of SCD1. In this review we discuss perturbations in cell signaling and lipid metabolism cascades in insulin-sensitive tissues due to SCD1 deficiency. In particular, we address the role of cellular signaling molecules including free fatty acids, ceramides, fatty acyl-CoAs, AMP-activated protein kinase, protein tyrosine phosphatase 1B as well as of membrane fluidity. While the precise mechanism of SCD action on insulin signaling remains to be clarified, current findings on SCD point to a very promising novel target for the treatment of insulin resistance.
Laboratory of Cell Signaling and Metabolic Disorders, Nencki Institute of Experimental Biology, 3 Pasteura St., 02-093 Warsaw, Poland.
Pawel
P
Dobrzyn
Magdalena
M
Jazurek
Agnieszka
A
Dobrzyn
D000818:Animals; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase