Short-term effects of tumor necrosis factor on energy and substrate metabolism in dogs

In vivo short-term effects of recombinant human TNF-alpha on lipolysis, FFA flux, fat oxidation, triglyceride-fatty acid cycling, and glucose kinetics were evaluated with stable isotopic tracers and indirect calorimetry along with monitoring of hemodynamic parameters in fasted dogs. High-dose TNF infusion (10 micrograms/kg) caused a fall in mean arterial pressure (P < 0.01), pulmonary arterial pressure (P < 0.001), and cardiac index (CI) (P < 0.05). The rate of appearance of glycerol (Ra glycerol) and the rate of appearance of FFA (Ra FFA) were decreased by 20% (P < 0.05) and by 42% (P < 0.01), respectively. Total fat oxidation fell by 23% (P < 0.05). In contrast, TNF infusion significantly increased glucose production by 13% (P < 0.05) and metabolic clearance rate of glucose by 25% (P < 0.01). However, TNF infusion did not change energy expenditure. Low-dose TNF infusion (3.5 micrograms/kg) caused changes similar in all respects, except magnitude, to the high-dose effects. There was a significant correlation between percent change of CI (delta CI) and percent change of rate of appearance of palmitate (Ra palmitate; delta Ra palmitate) (P < 0.0001, r = 0.69), Ra FFA (delta Ra FFA) (P < 0.0001, r = 0.60), and Ra glycerol (delta Ra glycerol) (P < 0.0329, r = 0.36). The correlation between delta CI and delta Ra palmitate was greater than the correlation between delta CI and delta Ra glycerol (P = 0.028). We conclude that the acute response to TNF causes a shift towards carbohydrate as an energy substrate in a dose-dependent manner by both decreasing the availability of FFAs and increasing glucose production.