Metabolic effects of tumour necrosis factor alpha in NMRI mice

Following a single injection of 7.5 x 10(7) U kg-1 of human recombinant tumour necrosis factor-alpha (TNF-alpha) to female NMRI mice, marked hypoglycaemia was observed within a 2 h period, accompanied by a severe depletion of liver glycogen and a drop in rectal body temperature when compared with pair-fed controls. There was no alteration in plasma alanine, lactate or pyruvate values, but an elevation of acetoacetate and 3-hydroxybutyrate when compared with pair-fed controls. Production of 14CO2 from U-14C-glucose was reduced in TNF-alpha treated animals, while production of 14CO2 from U-14C-palmitate was not significantly different from controls, suggesting that the glucose was not being used to provide an increased metabolic rate. Glucose utilisation by different tissues was investigated by the 2-deoxyglucose tracer method. This showed that 2 h following TNF-alpha infusion glucose utilisation was increased in colon, liver, kidney and spleen by 500, 350, 36 and 25% respectively. However, when calculated on a whole-animal basis the major contributor to the increased glucose consumption was the liver. Plasma levels of both FFA and triglycerides were also elevated in TNF-alpha treated animals, suggesting that increased consumption of glucose by the liver may be utilised for lipogenesis. The rate of conversion of glucose into lipids in the liver was more than doubled 2 h after TNF-alpha administration with a concomitant rise in plasma and adipose tissue. These results suggest that administration of TNF-alpha produces a severe hypoglycaemia in order to serve an increased lipogenesis in liver and adipose tissue, which appears to be independent of the anorectic effect.