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


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.


CONCLUSIONS
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.
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto, Japan.
Kentaro
K
Kaneko
Michael
M
Lazarus
Chihiro
C
Miyamoto
Yo
Y
Oishi
Nanae
N
Nagata
Shuzhang
S
Yang
Masaaki
M
Yoshikawa
Kosuke
K
Aritake
Tomoyuki
T
Furuyashiki
Shuh
S
Narumiya
Yoshihiro
Y
Urade
Kousaku
K
Ohinata
D000284:Administration, Oral; D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000187:drug effects*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists; D012273:Ribulose-Bisphosphate Carboxylase / Q000008:administration & dosage / Q000494:pharmacology*
D054834:Lipocalins; D008565:Membrane Proteins; D009478:Neuropeptide Y; D010446:Peptide Fragments; D017465:Receptors, Opioid, delta; C443993:rubiscolin 6; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D012273:Ribulose-Bisphosphate Carboxylase; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase