Agouti-Related Protein Segments Outside of the Receptor Binding Core Are Required for Enhanced Short- and Long-term Feeding Stimulation

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• 作者：Michael E. Madonna ; Jennifer Schurdak ; Ying-kui Yang ; Stephen Benoit ; Glenn L. Millhauser
• 刊名：ACS Chemical Biology
• 出版年：2012
• 出版时间：February 17, 2012
• 年：2012
• 卷：7
• 期：2
• 页码：395-402
• 全文大小：430K
• 年卷期：v.7,no.2(February 17, 2012)
• ISSN：1554-8937

文摘

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.