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109 AGOUTI-RELATED PEPTIDE AMELIORATES LONG-TERM SUPPRESSION OF FOOD INTAKE FOLLOWING INTERLEUKIN-1β ADMINISTRATION TO THE BRAINSTEM.
  1. M. DeBoer1,
  2. D. L. Marks1
  1. 1Department of Pediatrics, Oregon Health & Science University, Portland, OR.

Abstract

Cachexia involves an anorexic response to proinflammatory diseases such as cancer, acquired immune deficiency syndrome (AIDS), and cystic fibrosis. Prior experiments have implicated the involvement of hypothalamic neurons producing pro-opiomelanocortin (POMC) that release α-melanocyte stimulating hormone, which then acts on melanocortin-4 receptors (MC4R) to produce a decrease in appetite. The nucleus of the solitary tract (NTS) in the brainstem-which also contains POMC neurons and is involved in many autonomic responses, such as gastric motility and response to taste-is likely to be involved in producing some of the symptoms of cachexia. Its response to inflammation, however, is not currently known. We hypothesized that administration of interleukin (IL)-1β to the fourth ventricle overlying the NTS would result in short-term anorexia, which would be blocked via the use of agouti-related peptide (AgRP), a natural antagonist of the MC4R. We placed intracerebroventricular (ICV) cannulas in the fourth ventricle of rats. One hour prior to lights-out, we administered artificial cerebrospinal fluid (aCSF) or AgRP. Then just prior to lights-out, we injected aCSF or IL-1β and measured 3-hour and 12-hour food intake in these animals. In a separate experiment, we sacrificed and perfused three groups of rats: those who had received two injections of aCSF, those who had received an injection of aCSF prior to IL-1β 1 hour prior to sacrifice, and those who received AgRP followed by IL-1β prior to sacrifice. We performed double-label immunohistochemistry using fluorescent tracers to identify neurons expressing tyrosine hydroxylase and c-fos, a marker of neuronal activation. Rats who received injections of IL-1β exhibited a decrease in 3-hour and 12-hour food intake compared with rats treated with aCSF alone (−73% vs control at 3 hours [p < .001], −44% at 12 hours [p < .001]). Rats pretreated with AgRP before receiving IL-1β exhibited a decrease in food intake at the 3-hour time point but a normalization of food intake by the 12-hour time point (−60% at 3 hours [p < .001], −6% at 12 hours [p > .05]). Rats treated with AgRP followed by aCSF did not differ in food intake from the control animals. Immunohistochemistry showed no significant difference in c-fos activation of neurons expressing tyrosine-hydroxylase immunoreactivity, although there was a trend toward a significant increase in activation in TH neurons (47% for control vs 59% for TH [p = .055]). IL-1β administration to the fourth ventricle produces anorexia, which is ameliorated by preadministration of AgRP. This may involve activation of neurons expressing tyrosine hydroxylase, although further experiments are needed to establish their role in the process.

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