We examined the in vivo contribution of insulin, T090137 (T09), agonist of liver X receptor (LXR), fenofibrate, agonist of peroxisome proliferator activated receptor (PPAR-α) and sterol regulatory element binding protein-1c (SREBP-1c) on the unsaturated fatty acid synthesis controlled by Δ6 and Δ5 desaturases, compared with the effects on stearoylcoenzyme A desaturase-1. When possible they were checked at three levels: messenger RNA (mRNA), desaturase protein and enzymatic activity. In control rats, only fenofibrate increased the insulinemia that was maintained by the simultaneous administration of T09, but this increase has no specific effect on desaturase activity. T09 enhanced SREBP-1 in control animals and the mRNAs and activity of the three desaturases in control and type-1 diabetic rats, demonstrating a LXR/SREBP-1-mediated activation independent of insulin. However, simultaneous administration of insulin and T09 to diabetic rats led to a several-fold increase of the mRNAs of the desaturases, suggesting a strong synergic effect between insulin and LXR/retinoic X receptor (RXR). Moreover, this demonstrates the existence of an interaction between unsaturated fatty acids and cholesterol metabolism performed by the insulin/SREBP-1c system and LXR/RXR. PPAR-α also increased the expression and activity of the three desaturases independently of the insulinemia since it was equivalently evoked in streptozotocin diabetic rats. Besides, PPAR-α increased the palmitoylcoenzyme A elongase, evidencing a dual regulation in the fatty acid biosynthesis at the level of desaturases and elongases. The simultaneous administration of fenofibrate and T09 did not show additive effects on the mRNA expression and activity of the desaturases. Therefore, the results indicate a necessary sophisticated interaction of all these factors to produce the physiological effects.Instituto de Investigaciones Bioquímicas de La Plata