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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
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