Orally administered rubiscolin-6, a δ opioid peptide derived from Rubisco, stimulates food intake via leptomeningeal lipocallin-type prostaglandin D synthase in mice.

SCOPE: We found that rubiscolin-6, a δ opioid agonist peptide derived from d-ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), a major protein of green leaves, stimulates food intake after oral administration in mice. We therefore investigated its mechanism. METHODS AND RESULTS: Orexigenic activity after oral administration of rubiscolin-6 was blocked by central administration of naltrindole, an antagonist for δ opioid receptor, suggesting that orally administered rubiscolin-6 stimulates food intake via central δ opioid receptor activation. The orexigenic activity of rubiscolin-6 was inhibited by celecoxib, a cyclooxygenase (COX)-2 inhibitor. The hypothalamic mRNA expression of COX-2 and lipocallin-type (L) prostaglandin D synthase (PGDS) was elevated in response to rubiscolin-6 administration. Rubiscolin-6 stimulated food intake in wild-type and hematopoietic (H)-PGDS knockout (KO), but not L-PGDS KO mice. Interestingly, rubiscolin-6 stimulated food intake in L-PGDS(flox) /Nescre mice, which were deficient in L-PGDS in the brain parenchyma, but not leptomeninges. The orexigenic effect of rubiscolin-6 was abolished by genetic deletion of DP(1) receptor for PGD(2) , and by MK0524 or BIBO3304, an antagonist of DP(1) receptor or of Y(1) receptor for neuropeptide Y, respectively. CONCLUSION: Orally administered rubiscolin-6 may stimulate food intake through COX-2 and leptomeningeal L-PGDS, followed by DP(1) and Y(1) receptors, downstream of the central δ opioid receptor.