Endotoxin (lipopolysaccharide [LPS]) stimulates the production of cytokines, which mediate many of the metabolic effects associated with infection. In LPS-sensitive C57B1/6 mice, LPS doses as low as 0.01 fig per mouse decreased adipose tissue lipoprotein lipase (LPL) activity by greater than 50%. In LPS-resistant C3H/HeJ mice, which do not produce cytokines in response to LPS, doses of LPS as high as 10 fig per mouse did not affect LPL activity in adipose tissue. In muscle of C57B1/6 mice, LPL activity was decreased by 27% after 10 fig of LPS, whereas in C3H/HeJ mice there was no effect. These results indicate that the LPS-induced decrease in both adipose and muscle LPL activity is mediated by cytokines. Tumor necrosis factor (TNF), interleukin (IL)-l, leukemia-inhibiting factor (LJF), interferon alfa, and interferon gamma all decreased adipose tissue LPL activity in intact mice. In skeletal and cardiac muscle, only IL-1 and interferon gamma decreased LPL activity, whereas TNF, LJF, and interferon alfa had no effect. Inhibition of TNF activity blocked the increase in serum triglycerides that is characteristically observed after LPS but did not affect the ability of B acterial, viral, and parasitic infections are frequently associated with hypertriglyceridemia secondary to elevations in very-low-density lipoprotein (VLDL) levels.14 Endotoxin (LPS) administration, which mimics Gram-negative bacterial infections, has been shown to produce hypertriglyceridemia by stimulating the hepatic production of VLDL and/or by inhibiting the clearance of triglyceride-rich lipoproteins.3 -5 - 6 The activity of lipoprotein lipase (LPL), a key regulatory enzyme in the catabolism and clearance of triglyceride-rich lipoproteins, is decreased after LPS treatment in both adipose tissue and muscle.5 ' 7 ' 8 -10 Recent studies have suggested that the decrease in adipose tissue LPL activity is due to a posttranslational effect.
11Infection and LPS administration stimulate the production of a large number of cytokines, the hormones of the immune system, and these cytokines are thought to mediate many of the metabolic effects associated with infection and LPS treatment. In adipocytes in culture, studies by our and other laboratories have demonstrated that many cytokines, including tumor necrosis factor (TNF), interleukin (IL)-l, IL-6, IL-11, leukemiainhibiting factor (LJF), interferon alfa (IFN-a) The purpose of the present study was to determine the following: (1) whether the LPS-induced decrease in adipose and muscle LPL activity requires cytokine production; to determine this we used HeJ mice, which do not produce cytokines in response to LPS 22 -23 ; (2) the effect of TNF, IL-1, LIF, IFN-a, and IFN-yon adipose and muscle LPL activity in intact mice; and (3) whether either TNF or IL-1, the major cytokines produced in response to LPS administration, mediate the LPSinduced changes in LPL activity.
Methods MaterialsTritiated triolein was purchased from New England Nuclear. Triolein, lecithin, and fatty acid-free bovine serum album...