The objective of these studies was to demonstrate that the reduction in lipogenic enzymes caused by ingestion of dietary polyunsaturated fat can in part be attributed to an inhibition of triiodothyronine's induction of hepatic lipogenic enzymes. A 3 x 4 factorial design was employed to examine the effect of diets containing no fat, beef tallow or safflower oil on the triiodothyronine-mediated (0, 2, 4 or 8 micrograms/100 g injected daily intraperitoneally) induction of rat liver lipogenic enzymes. Triiodothyronine (T3) administration induced (p less than 0.05) the activity of malic enzyme, fatty acid synthase and glucose-6-phosphate dehydrogenase in a dose-dependent manner. Malic enzyme activity was increased five- to sevenfold by 8 micrograms T3/100 g daily. Fatty acid synthase activity at the 8 micrograms dose had increased two- to threefold whereas glucose-6-phosphate dehydrogenase activity was elevated only 15-35%. Beef tallow and safflower oil supplementation of the high glucose, fat-free diet significantly reduced the T3 induction of all the enzymes. Safflower oil was more effective than tallow as a repressor of T3 action. The effect of dietary fat, particularly safflower oil, was to increase the amount of T3 required to induce the activity of lipogenic enzymes. In a second study, with a 2 x 2 factorial design, daily injection of 15 micrograms T3/100 g was found to overcome the safflower oil inhibition of lipogenic enzymes. These data support the hypothesis that polyunsaturated fats uniquely suppress the gene expression of lipogenic enzymes by functioning as competitive inhibitors of T3 action, possibly at the nuclear receptor level.