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

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.

SUBMITTER: Madonna ME

PROVIDER: S-EPMC3288358 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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

Madonna Michael E ME Schurdak Jennifer J Yang Ying-Kui YK Benoit Stephen S Millhauser Glenn L GL

ACS chemical biology 20111230 2

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. O ...[more]

PMID: 22129136

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

Publications

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

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