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Agouti-related protein segments outside of the receptor binding core are required for enhanced short- and long-term feeding stimulation.

Authors
  • Madonna, Michael E1
  • Schurdak, Jennifer
  • Yang, Ying-Kui
  • Benoit, Stephen
  • Millhauser, Glenn L
  • 1 Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064, United States. , (United States)
Type
Published Article
Journal
ACS Chemical Biology
Publisher
American Chemical Society
Publication Date
Feb 17, 2012
Volume
7
Issue
2
Pages
395–402
Identifiers
DOI: 10.1021/cb2003412
PMID: 22129136
Source
Medline
Language
English
License
Unknown

Abstract

The agouti-related protein (AgRP) plays a central role in energy balance by reducing signaling through the hypothalamic melanocortin receptors (McRs) 3 and 4, in turn stimulating feeding and decreasing energy expenditure. Mature AgRP(83-132), produced by endoproteolytic processing, contains a central region that folds as an inhibitor cystine knot (ICK) stabilized by a network of disulfide bonds; this domain alone carries the molecular features for high affinity McR binding and inverse agonism. Outside of the ICK domain are two polypeptide segments, an N-terminal extension and a C-terminal loop, both completely conserved but of unknown function. Here we examine the physiological roles of these non-ICK segments by developing a panel of modified AgRPs that were administered to rats through intracerebroventricular (ICV) injection. Analysis of food consumption demonstrates that basic (positively charged) residues are essential for potent short- and long-term AgRP stimulated feeding. Moreover, we demonstrate an approximate linear relationship between protein charge density and 24 h food intake. Next, we developed artificial AgRP(83-132) analogues with increased positive charge and found that these species were substantially more potent than wild type. A single dose of one protein, designated AgRP-4K, results in enhanced feeding for well over a week and weight gain that is nearly double that of AgRP(83-132). These studies suggest new strategies for the development of potent orexigenic species and may serve as leads for the development of therapeutics for treating wasting conditions such as cachexia.

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