Rosiglitazone Increases Indexes of Stearoyl-CoA Desaturase Activity in Humans Link to Insulin Sensitization and the Role of Dominant-Negative Mutation in Peroxisome Proliferator–Activated Receptor-

Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator–activated receptor(PPAR ) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and 6and 5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and 5-desaturase but not 6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r 0.73, P < 0.05). In the P467L PPAR carrier, SCD and 5-desaturase activity indexes were exceptionally low but were restored (52and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPAR mutation supports a pivotal role of PPAR function in SCD regulation. Diabetes 54:1379–1384, 2005