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Originally published In Press as doi:10.1074/jbc.M008499200 on October 18, 2000

J. Biol. Chem., Vol. 276, Issue 2, 1466-1473, January 12, 2001
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Impaired Prohormone Convertases in Cpefat/Cpefat Mice*

Yemiliya BermanDagger , Nino Mzhavia, Ann Polonskaia, and Lakshmi A. Devi§

From the Department of Pharmacology and § Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016

A spontaneous point mutation in the coding region of the carboxypeptidase E (CPE) gene results in a loss of CPE activity that correlates with the development of late onset obesity (Nagert, J. K., Fricker, L. D., Varlamov, O., Nishina, P. M., Rouille, Y., Steiner, D. F., Carroll, R. J., Paigen, B. J., and Leiter, E. H. (1995) Nat. Genet. 10, 135-142). Examination of the level of neuropeptides in these mice showed a decrease in mature bioactive peptides as a result of a decrease in both carboxypeptidase and prohormone convertase activities. A defect in CPE is not expected to affect endoproteolytic processing. In this report we have addressed the mechanism of this unexpected finding by directly examining the expression of the major precursor processing endoproteases, prohormone convertases PC1 and PC2 in Cpefat mice. We found that the levels of PC1 and PC2 are differentially altered in a number of brain regions and in the pituitary. Since these enzymes have been implicated in the generation of neuroendocrine peptides (dynorphin A-17, beta -endorphin, and alpha - melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of these peptides in Cpefat and wild type animals. We found a marked increase in the level of dynorphin A-17, a decrease in the level of alpha -melanocyte-stimulating hormone, and an alteration in the level of C-terminally processed beta -endorphin. These results suggest that the impairment in the level of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activities and that this may lead to the development of obesity in these animals.

* This work is supported in part by National Institutes of Health Grants DA00342 (to Y. B.) and NS26880 and DA00458 (to L. A. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Pharmacology, New York University School of Medicine, New York, NY 10016. Tel.: 212-263-7119; Fax: 212-263-7133; E-mail: bermay01@med.nyu.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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