Tumor necrosis factor (TNF) administration produces an increase in plasma triglycerides that may be due to inhibition of adipose lipoprotein lipase activity and/or a stimulation of hepatic lipogenesis. We now report that TNF administration to insulinopenic diabetic rats increases serum triglycerides (2 h, 2.4-fold; 17 h, 4.3-fold). Adipose tissue lipoprotein lipase activity was markedly decreased in diabetic animals compared with controls and was not further inhibited by TNF. Incorporation of tritiated water into fatty acids in the liver was increased 45% 1-2 h after TNF and 87% at 16-17 h. These results indicate that the TNF-induced increase in circulating lipid levels can occur in the absence of a TNF-induced inhibition of adipose tissue lipoprotein lipase activity. Moreover, the clearance from the circulation of triglycerides in chylomicrons was similar in control and TNF-treated animals; these results provide further evidence that the removal of triglyceride-rich lipoproteins is not altered in the TNF-treated animals. Our data suggest that the TNF-induced stimulation of hepatic lipid synthesis may play an important role in the increase in serum triglycerides. In addition, TNF administration to diabetic animals leads to an elevation in serum glucose levels (73% at 17 h) without a change in serum insulin levels. Thus, TNF stimulation of hepatic lipogenesis is independent of changes in insulin.