Oxyntomodulin inhibits food intake in the rat

Oxyntomodulin is derived from proglucagon processing in the intestine and t he central nervous system. To date, no role in the central nervous system h as been demonstrated. We report here that oxyntomodulin inhibits refeeding when injected intracerebroventricularly and into the hypothalamic paraventr icular nucleus of 24-h fasted rats [intracerebroventricularly and into the paraventricular nucleus, 1 h, oxyntomodulin (1 nmol), 3.1 +/- 0.5 g; saline , 6.2 +/- 0.4 g; P < 0.005]. In addition, oxyntomodulin inhibits food intak e in nonfasted rats injected at the onset of the dark phase (intracerebrove ntricularly, I h: oxyntomodulin, 3 nmol, 1.1 +/- 0.19 g vs. saline, 2.3 +/- 0.2 g; P < 0.05). This effect of oxyntomodulin on feeding is of a similar time course and magnitude as that of an equimolar dose of glucagon-like pep tide-1. Other proglucagon-derived products investigated [glucagon, glicenti n (intracere-broventricularly, 3 nmol; into the paraventricular nucleus, 1 nmol), and spacer peptide-1 (intracerebroventricularly and into the paraven tricular nucleus, 3 nmol)] had no effect on feeding at any time point exami ned. The anorectic effect of oxyntomodulin (intracerebroventricularly, 3 nm ol; into the paraventricular nucleus, 1 nmol) was blocked when it was coadm inistered with the glucagon-like peptide-1 receptor antagonist, exendin-(9- 39) (intracerebroventricularly, 100 nmol; into the paraventricular nucleus, 10 nmol). However, oxyntomodulin has a lower affinity for the glucagon-lik e peptide-1 receptor compared with glucagon-like peptide-1 (IC50: oxyntomod ulin, 8.2 nM, glucagon-like peptide-1, 0.16 nM). One explanation for this i s that there might be an oxyntomodulin receptor to which exendin-(9-39) can also bind and act as an antagonist.