The peptide hemopressin acts through CB1 cannabinoid receptors to reduce food intake in rats and mice.
Hemopressin is a short, nine amino acid peptide (H-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His-OH) isolated from rat brain that behaves as an inverse agonist at the cannabinoid receptor CB(1), and is shown here to inhibit agonist-induced receptor internalization in a heterologous cell model. Since this peptide occurs naturally in the rodent brain, we determined its effect on appetite, an established central target of cannabinoid signaling. Hemopressin dose-dependently decreases night-time food intake in normal male rats and mice, as well as in obese ob/ob male mice, when administered centrally or systemically, without causing any obvious adverse side effects. The normal, behavioral satiety sequence is maintained in male mice fasted overnight, though refeeding is attenuated. The anorectic effect is absent in CB(1) receptor null mutant male mice, and hemopressin can block CB(1) agonist-induced hyperphagia in male rats, providing strong evidence for antagonism of the CB(1) receptor in vivo. We speculate that hemopressin may act as an endogenous functional antagonist at CB(1) receptors and modulate the activity of appetite pathways in the brain.
Dodd
Garron T
GT
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
Mancini
Giacomo
G
Lutz
Beat
B
Luckman
Simon M
SM
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D048588:Benzoxazines / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003511:Cyclohexanols; D004305:Dose-Response Relationship, Drug; D004327:Drinking Behavior / Q000187:drug effects; D013759:Dronabinol / Q000494:pharmacology; D004333:Drug Administration Routes; D004435:Eating / Q000187:drug effects* / Q000235:genetics; D005508:Food Deprivation / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006454:Hemoglobins / Q000494:pharmacology*; D006963:Hyperphagia / Q000139:chemically induced / Q000188:drug therapy; D020738:Leptin / Q000172:deficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011619:Psychotropic Drugs / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D000077285:Rimonabant; D013997:Time Factors; D014162:Transfection / Q000379:methods
D048588:Benzoxazines; D003511:Cyclohexanols; D006454:Hemoglobins; D020738:Leptin; D009025:Morpholines; D009281:Naphthalenes; D010446:Peptide Fragments; D010880:Piperidines; D011619:Psychotropic Drugs; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C485184:enhanced green fluorescent protein; C473218:hemopressin; D049452:Green Fluorescent Proteins; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant