Differential metabolic responses to tumor necrosis factor with increase in age

Abstract

Previous studies have shown varied responses to the effects of tumor necrosis factor (TNF) on glucose and lipid metabolism. To elucidate possible causes for this variation, the present study compared sequential changes in plasma glucose, lactic acid, triglyceride (TG), free fatty acids (FFA), and plasma insulin levels in 1.5- and 16-month-old, normal, fed, male rats, 1 to 6 hours after different doses of intravenous (IV) TNF. In addition, assessment was made of TNF injected intraperitoneally (IP) in precannulated and intact young (1.5 months) rats and of the dose-response (0.25 to50 μg/100 g rat) and the sensitivity to insulin in intact rats. Finally, the metabolic response and changes in serum insulin and corticosterone concentration after IP TNF were compared in 1.5-, 5-, and 16-month-old rats. Data show that metabolic responses vary with increase in age and experimental conditions. Dose-dependent decreases in plasma glucose (1.4 to 3.9 μmol/mL) and elevations in lactic acid (0.8 to 3.0 μmol/mL) were greater in 1.5- versus 16-month-old rats, were delayed in cannulated rats, and were preceded by hyperglycemia following larger IV doses. Plasma TG levels were elevated after TNF in all groups except precannulated rats, and also showed differences with age. In young rats, the elevation in TG peaked 2 hours after IP injection with return to baseline and was preceded by an elevation in FFA levels. In older rats, which were hypertriglyceridemic at base line, the elevation in TG by TNF occurred by suppressing the decrease in TG of controls, was not accompanied by an increase in FFA levels, was sustained for 5 hours, and was of greater magnitude than in young rats. Significant changes in plasma insulin did not occur in young and older rats after IV TNF. However, young rats had a significant decrease ( P < .02) in plasma insulin and an elevation in corticosterone levels after IP TNF, whereas older rats exhibited an increase in plasma insulin ( P < .02) and a comparable elevation in plasma corticosterone. Young rats also showed an increase in plasma insulin following IP TNF when hypoglycemia was prevented by the infusion of glucose. However, when insulin levels were held comparable (2.4 ng/mL), glucose uptake was enhanced ( P < .05) compared with controls. These findings indicate that mobilization of energy substrates occurs during the initial exposure to TNF, which is altered by the nutritional state of the rats and the dose and route of administration. In older rats, this metabolic response is modified in both magnitude and duration, possibly due to development of an increased resistance to insulin and differences in the effect of IP TNF on TG removal versus TG synthesis.