Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade.
Overexpression of agouti-related peptide (AgRP), an endogenous melanocortin (MC) 3 and 4 receptor antagonist (MC3/4-R), causes obesity. Exogenous AgRP-(83---132) increases food intake, but its duration and mode of action are unknown. We report herein that doses as low as 10 pmol can have a potent effect on food intake of rats over a 24-h period after intracerebroventricular injection. Additionally, a single third ventricular dose as low as 100 pmol in rats produces a robust increase in food intake that persists for an entire week. AgRP-(83---132) completely blocks the anorectic effect of MTII (MC3/4-R agonist), given simultaneously, consistent with a competitive antagonist action. However, when given 24 h prior to MTII, AgRP-(83---132) is ineffective at reversing the anorectic effects of the agonist. These results support a critical role of MC tone in limiting food intake and indicate that the orexigenic effects of AgRP-(83---132) are initially mediated by competitive antagonism at MC receptors but are sustained by alternate mechanisms.
Hagan
M M
MM
Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0559, USA. haganmm@email.uc.edu
Rushing
P A
PA
Pritchard
L M
LM
Schwartz
M W
MW
Strack
A M
AM
Van Der Ploeg
L H
LH
Woods
S C
SC
Seeley
R J
RJ
D054369:Agouti-Related Protein; D000818:Animals; D019167:Appetite Stimulants / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors*; D013995:Time; D000521:alpha-MSH / Q000031:analogs & derivatives
D054369:Agouti-Related Protein; D019167:Appetite Stimulants; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D011506:Proteins; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; C411703:agouti-related protein-(83-132); D000521:alpha-MSH