The ileal proglucagon-derived peptides (PGDPs) play important roles in the regulation of gastric function and insulin secretion. We have previously demonstrated the existence of a proximal-distal enteroendocrine loop mediated by glucose-dependent insulinotropic peptide (GIP), through which intestinal PGDP secretion is stimulated after placement of nutrients in the duodenum. To study the possible involvement of neuropeptides in this loop, we infused gastrin-releasing peptide (GRP) into anesthetized rats at 47, 235, or 470 ng/h. GRP stimulated secretion of the intestinal PGDPs only at the highest dose, from 250 +/- 18 to 321 +/- 9 pg/ml (P < 0.05). Gastrin secretion was also increased by GRP infusion (from 20 +/- 7 to 75 +/- 19 pg/ml; P < 0.05); however, GIP release was not altered from basal levels. Placement of fat into the duodenum stimulated the secretion of both the intestinal PGDPs and GIP (to 618 +/- 221 and 417 +/- 154 pg/ml above basal, respectively; P < 0.05). However, infusion of the GRP antagonist, BW10 (3 ng/h), completely abrogated the PGDP response to duodenal fat (P < 0.05). In contrast, the GIP response was reduced by 56 +/- 15% (P < 0.05) with BW10 administration, but remained elevated compared to the basal level (P < 0.05). Removal of the entire intestine distal to the fat-infused duodenal segment prevented the rise in intestinal PGDPs, but not that of GIP, demonstrating the distal and proximal origins of these peptides, respectively. Thus, placement of fat into the duodenum stimulated the release of the PGDPs from the distal intestine through a GRP-dependent mechanism. Although GIP plays a role in regulating intestinal PGDP secretion in the rat, GRP appears to exert its effects independent of changes in GIP.