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

ScopeWe found that rubiscolin-6, a d 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 resultsOrexigenic activity after oral administration of rubiscolin-6 was blocked by central administration of naltrindole, an antagonist for d opioid receptor, suggesting that orally administered rubiscolin-6 stimulates food intake via central d 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-PGDSflox/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 DP1 receptor for PGD2, and by MK0524 or BIBO3304, an antagonist of DP1 receptor or of Y1 receptor for neuropeptide Y, respectively. ConclusionOrally administered rubiscolin-6 may stimulate food intake through COX-2 and leptomeningeal L-PGDS, followed by DP1 and Y1 receptors, downstream of the central d opioid receptor.