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

被引:256
作者
Hagan, MM
Rushing, PA
Pritchard, LM
Schwartz, MW
Strack, AM
Van der Ploeg, LHT
Woods, SC
Seeley, RJ
机构
[1] Univ Cincinnati, Med Ctr, Dept Psychiat, Cincinnati, OH 45267 USA
[2] Univ Washington, Harborview Med Ctr, Dept Med, Seattle, WA 98195 USA
[3] Univ Washington, Harborview Med Ctr, Puget Sound Vet Affairs Hlth Care Syst, Seattle, WA 98195 USA
[4] Merck Res Labs, Dept Anim Pharmacol, Rahway, NJ 07065 USA
[5] Merck Res Labs, Dept Obes Res, Rahway, NJ 07065 USA
关键词
MTII; obesity; arcuate nucleus; hyperphagia; hypothalamus; alpha-melanocyte-stimulating hormone;
D O I
10.1152/ajpregu.2000.279.1.R47
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页码:R47 / R52
页数:6
相关论文
共 43 条
[1]   The neuropeptide Y agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice [J].
Broberger, C ;
Johansen, J ;
Johansson, C ;
Schalling, M ;
Hökfelt, T .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (25) :15043-15048
[2]   EVIDENCE THAT BETA-ENDORPHIN IS SYNTHESIZED IN CELLS IN THE NUCLEUS-TRACTUS-SOLITARIUS - DETECTION OF POMC MESSENGER-RNA [J].
BRONSTEIN, DM ;
SCHAFER, MKH ;
WATSON, SJ ;
AKIL, H .
BRAIN RESEARCH, 1992, 587 (02) :269-275
[3]   NEUROPEPTIDE-Y AND HUMAN PANCREATIC-POLYPEPTIDE STIMULATE FEEDING-BEHAVIOR IN RATS [J].
CLARK, JT ;
KALRA, PS ;
CROWLEY, WR ;
KALRA, SP .
ENDOCRINOLOGY, 1984, 115 (01) :427-429
[4]   Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti [J].
Dinulescu, DM ;
Fan, W ;
Boston, BA ;
McCall, K ;
Lamoreux, ML ;
Moore, KJ ;
Montagno, J ;
Cone, RD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (21) :12707-12712
[5]  
Elias CF, 1998, J COMP NEUROL, V402, P442, DOI 10.1002/(SICI)1096-9861(19981228)402:4<442::AID-CNE2>3.0.CO
[6]  
2-R
[7]   Role of melanocortinergic neurons in feeding and the agouti obesity syndrome [J].
Fan, W ;
Boston, BA ;
Kesterson, RA ;
Hruby, VJ ;
Cone, RD .
NATURE, 1997, 385 (6612) :165-168
[8]  
Flynn MC, 1999, PHYSIOL BEHAV, V65, P901
[9]   ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors [J].
Fong, TM ;
Mao, C ;
MacNeil, T ;
Kalyani, R ;
Smith, T ;
Weinberg, D ;
Tota, MR ;
VanderPloeg, LHT .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 237 (03) :629-631
[10]   Feeding effects of hypothalamic injection of melanocortin 4 receptor ligands [J].
Giraudo, SQ ;
Billington, CJ ;
Levine, AS .
BRAIN RESEARCH, 1998, 809 (02) :302-306