We have previously shown that administration of tumor necrosis factor-alpha (TNF alpha) to intact rats results in an acute (within 60-120 min) stimulation of hepatic fatty acid synthesis, which persists for an extended period. Hepatic cholesterol synthesis is also stimulated by 16-17 h after TNF alpha treatment. We now demonstrate, using intact mice, that stimulation of hepatic lipid synthesis is not solely the property of the cytokine TNF alpha. Incorporation of 3H2O into fatty acids in the liver was increased 60-120 min and 16-17 h after the administration of TNF beta, interleukin-1 (IL-1), and interferon-alpha (IFN alpha). TNF alpha, IL-1, and IFN alpha all rapidly stimulate hepatic fatty acid synthesis (within 0-30 min), with the peak occurring at 60-120 min. The half-maximal doses of TNF alpha (200 ng) and IL-1 (20 ng) that stimulate hepatic fatty acid synthesis are similar to those that induce fever, a well recognized biological effect of these cytokines. Additionally, hepatic cholesterol synthesis was increased 16-17 h after TNF beta, IL-1, and IFN gamma treatment. The present study demonstrates that multiple cytokines from different cell types which act through different receptors can stimulate hepatic fatty acid and cholesterol synthesis. Previous studies have shown that multiple cytokines can inhibit the synthesis and storage of fat in cultured adipose cells. Taken together, these data indicate that multiple signals to perturb lipid metabolism may be produced as a consequence of an immunological or inflammatory response.