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This version published online on December 29, 2005
Endocrinology, doi:10.1210/en.2005-1373
A more recent version of this article appeared on April 1, 2006
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Submitted on October 28, 2005
Accepted on December 20, 2005

Agouti-related protein is post-translationally cleaved by proprotein convertase 1 to generate AGRP83-132: Interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan 3

John W.M. Creemers, Lynn E. Pritchard, Amy Gyte, Philippe Le Rouzic, Sandra Meulemans, Sharon L. Wardlaw, Xiaorong Zhu, Donald F. Steiner, Nicola Davies, Duncan Armstrong, Catherine B. Lawrence, Simon M. Luckman, Catherine A. Schmitz, Rick A. Davies, John C. Brennand, and Anne White*

Department of Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, B-3000 Leuven, Belgium. School of Medicine and Faculty of Life Sciences, University of Manchester, Stopford Building, Manchester M13 9PT, UK. Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street New York, NY 10032, USA. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA. AstraZeneca, Mereside, Alderley Park, Cheshire SK10 4TG, UK

* To whom correspondence should be addressed. E-mail: awhite{at}man.ac.uk.

Agouti-related protein (AGRP) plays a key role in energy homeostasis. The carboxyl-terminal domain of AGRP acts as an endogenous antagonist of the melanocortin-4 receptor (MC4-R). It has been suggested that the amino-terminal domain of AGRP binds to syndecan-3, thereby modulating the effects of carboxyl-terminal AGRP at the MC4-R. This model assumes that AGRP is secreted as a full-length peptide. In this study we have found that AGRP is processed intracellularly after Arg79-Glu80-Pro81-Arg82. The processing site suggests cleavage by proprotein convertases (PCs). RNA interference and overexpression experiments showed that PC1/3 is primarilarly responsible for cleavage in vitro, although both PC2 and PC5/6A can also process AGRP. Dual in situ hybridization demonstrated that PC1/3 is expressed in AGRP neurons in the rat hypothalamus. Moreover, hypothalamic extracts from PC1-null mice contained 3.3 fold more unprocessed full-length AGRP compared with wild-type mice, based on combined HPLC and RIA analysis, demonstrating that PC1/3 plays a role in AGRP cleavage in vivo. We also found that AGRP83-132 is more potent an antagonist than full-length AGRP, based on cAMP reporter assays, suggesting that post-translational cleavage is required to potentiate the effect of AGRP at the MC4-R. As AGRP is cleaved into distinct amino-terminal and carboxyl-terminal peptides, we tested whether amino-terminal peptides modulate food intake. However, intracerebroventricular (icv) injection of rat AGRP25-47 and AGRP50-80 had no effect on body weight, food intake or core body temperature. As AGRP is cleaved before secretion, syndecan-3 must influence food intake independently of the MC4-R.
Key words: Agouti-related protein • Melancortin-4 receptor • Proprotein convertase 1




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