While diabetes has traditionally been thought of as a disorder of carbohydrate metabolism, more recent work has indicated that diabetes is also a disease of lipid metabolism. Increased deposition of lipid in tissues other than white adipose leads to insulin resistance and the development of diabetes. One of the proposed reasons is that excess lipids, particularly lipids that are deposited in insulin-sensitive cell types other than adipocytes, can inhibit insulin signaling. The precise identity of the lipid factor responsible is not known, although free fatty acids, fatty acyl-CoA, diacylglycerol and ceramide are likely suspects. By activating protein kinase C, the lipid molecules seem to reduce the activity of insulin receptor substrate 1 (IRS-1), a key component of the insulin signaling pathway. Altered lipid metabolism in skeletal muscle as seen in the insulin-resistant states largely depend on the aberrant expression of genes encoding metabolic key enzymes. Consequently, regulators of tissue specific metabolic pathways are attractive candidates for novel therapeutic intervention strategies, but are still mostly unexplored. In recent years, several candidate genes have been proposed as therapeutic targets. Stearoyl-CoA desaturase1 (SCD1) is of special significance, because SCD1 is the major gene target of leptin, the central mediator in an endocrine circuit regulating energy homeostasis. SCD has been established by my previous studies as a new critical regulatory switch in the control of metabolic pathways and the maintenance of body weight. Using stearoyl-CoA desaturase null mouse model we have demonstrated that SCD plays a major role in the regulation of lipid and carbohydrate metabolism as well as in the development of obesity and diabetes. By aberrantly affecting expression of key metabolic enzymes in the liver, the SCD1 deficiency promotes fatty acid oxidation and thus represents a critical molecular checkpoint for maintenance of hepatic lipid homeostasis. We have shown that mice with a targeted disruption of the SCD1 gene have improved glucose tolerance compared to wild-type mice, despite lower fasting plasma insulin levels. Our studies established that in skeletal muscle and in brown adipose tissue, basal tyrosine phosphorylation of the IRS1 and IRS2, the association of both IRS1 and IRS2 with the ap85 subunit of phosphatidyl-inositol 3-kinase, the phosphorylation of Akt and membrane GLUT4 translocation are all elevated in SCD1-/- mice compared with wild-type mice. The precise mechanism of SCD action on insulin signaling remains to be established, however, our findings on SCD point to a very promising novel strategy for the treatment of obesity and insulin resistance.

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1. Stearoyl-CoA desaturase 1 deficiency decreases fatty acid oxidation in the heart