Interleukin (IL)-1 beta, IL-8, and tumor necrosis factor-alpha (TNF-alpha) induce anorexia when administered intracerebroventricularly at doses that yield estimated pathophysiological concentrations reported in the cerebrospinal fluid (CSF). Our hypothesis is that pivotal cytokines released during pathological processes interact to induce anorexia during disease. In the present study, we investigated the effects of the intracerebroventricular microinfusion of individual or multiple combinations (8 dyads and 5 triads) of IL-1 beta, IL-8, and TNF-alpha on feeding and the microstructure of eating in rats maintained ad libitum. Estimated pathophysiological concentrations of cytokine combinations exhibited additive or synergistic activities in inducing anorexia. Computerized analysis of behavioral patterns demonstrated that the most effective treatment (triad of 1.0 ng IL-1 beta + 20 ng IL-8 + 20 ng TNF-alpha/rat, n = 11) decreased nighttime meal size by 42% and feeding rate (meal size/meal duration) by 26%, whereas it increased the satiety ratio (postprandial intermeal intervals/meal size) by 80%; meal duration and meal frequency were not significantly affected. Analysis of meal parameters in 4-h intervals revealed a maximum effect during the first 4-h interval after the intracerebroventricular administration. The time course during this initial 4-h interval analyzed in 10-min periods was similar for IL-8 (n = 10) and TNF-alpha (n = 11), and both were significantly different from the time course induced by IL-1 beta (n = 10) and the most effective triad (n = 11). Intracerebroventricular microinfusion of heat-inactivated triad or intraperitoneal administration of the most effective triad, in doses-equivalent to those administered centrally, had no effect on feeding. The results suggest that estimated pathophysiological concentrations of cytokines in the CSF act centrally and additively or synergistically to decrease feeding, and this effect may participate in the anorexia frequently accompanying pathological processes.
SELL1 AND GAYATRI SONTI. Differential responsiveness of obese (falfa) and lean (FalFa) Zucker rats to cytokine-induced anorexia. Obes Res. 1997;5:3642. Pathophysiological and pharmacological concentrations of tumor necrosis factor-a (TNF-a) and interleukin-lp (IL-1p) in the cerebrospinal fluid (CSF) induce anorexia in normal rats. Obesity in humans and rodents is associated with increased TNF-a messenger RNA and protein levels in various cell types. This suggests that obese individuals may have differential regulation of cytokine production and dissimilar responsiveness to cytokines. In the present study, we investigated the effects of the intracerebroventricular (ICV) microinfusion of TNF-a (50, 100, and 500 ng/rat), IL-1p (1.0, 4.0, and 8.0 ng), and TNF-a (100 ng) plus IL-1p (1.0 ng) on obese (falfa) and lean (FalFa) Zucker rats. The results show that: TNF-a and IL-lp, and the concomitant administration of TNF-a and IL-1p decreased the short-term (4 hours), nighttime (12 hours), and total daily food intakes in obese and lean rats; IL-1p was more potent relative to TNF-a; obese rats showed greater responsiveness to ILlp: 8.0 ng IL-lp, for example, decreased the 12-hour food intake by 52% in obese and 22% in lean rats. On the other hand, obese and lean rats did not exhibit a significantly different responsiveness to the anorexia induced by 50,100, or 500 ng TNF-a at the 4-hour period; and the concomitant ICV administration of TNF-a and IL-lP induced anorexia with additive (4-hour period) or synergistic (12-hour and 24-hour periods) effects in PLATA-SALAMAN, CARLOS R, JOSEPH R VAS- obese rats. The effect of TNF-a plus IL-1p in lean rats was greater than additive for the 12-hour and 24-hour periods. The difference in suppression of total daily food intake by TNF-a plus IL-lfl in obese (-43%) versus lean (-23%) rats was significantly different (PcO.01). The results show that obese (fa@) and lean (FdFa) Zucker rats have differential responsiveness to the ICV microinfusion of two different classes of cytokines.
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