Long-term orexigenic effects of AgRP-(83---132) involve mechanisms other than melanocortin receptor blockade

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 279; no. 1; pp. 47 - R52
• Main Authors: Hagan, Mary M, Rushing, Paul A, Pritchard, Laurel M, Schwartz, Michael W, Strack, Alison M, Van der Ploeg, Lex H. T, Woods, Stephen C, Seeley, Randy J
• Format: Journal Article
• Language: English
• Published: United States 01.07.2000
• Subjects: Agouti-Related Protein; alpha-MSH - analogs & derivatives; Animals; Appetite Stimulants - pharmacology; Body Weight - drug effects; Dose-Response Relationship, Drug; Eating - drug effects; Intercellular Signaling Peptides and Proteins; Oligopeptides - administration & dosage; Oligopeptides - antagonists & inhibitors; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Proteins - pharmacology; Rats; Rats, Long-Evans; Receptor, Melanocortin, Type 3; Receptor, Melanocortin, Type 4; Receptors, Corticotropin - antagonists & inhibitors; Time
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.2000.279.1.r47

1  Department of Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0559; 2  Department of Medicine and Puget Sound Veterans Affairs Health Care System, Harborview Medical Center, University of Washington, Seattle, Washington 98195; and 3  Departments of Animal Pharmacology and Obesity Research, Merck Research Laboratories, Rahway, New York 07065 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. MTII; obesity; arcuate nucleus; hyperphagia; hypothalamus; -melanocyte-stimulating hormone