Abstract
The fat mouse strain exhibits a late-onset obesity syndrome associated with a mutation in the gene encoding carboxypeptidase E (CPE). CPE plays a central role in the biosynthesis of many regulatory peptides. Therefore, we examined the processing of procholecystokinin (proCCK) in the brain (neurons) and small intestine (endocrine cells) of fat/fat mice. In the brain, bioactive CCK was markedly reduced (7.9±1.0 pmol/g in fat/fat mice vs. 82.5±11.2 pmol/g in controls), but the concentration of the CPE substrate, glycyl-arginine-extended CCK, was elevated 105-fold. In contrast, the concentration of bioactive CCK in intestinal endocrine cells was unaffected. Endocrine cell processing was, nevertheless, altered with a 33-fold increase in glycyl-arginine-extended CCK. Interestingly, although total proCCK products were normal in the brain they were elevated 3-fold in the intestine, indicating that biosynthesis is upregulated in endocrine cells but not neurons to compensate for the processing defect. These results demonstrate that the CPE mutation differentially affects CCK processing in these two cell types. Intestinal CCK synthesis more closely resembles progastrin processing, suggesting the presence of an endocrine-specific biosynthetic regulatory mechanism not present in neurons. Copyright (C) 1998 Federation of European Biochemical Societies.
Originalsprog | Engelsk |
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Tidsskrift | FEBS Letters |
Vol/bind | 436 |
Udgave nummer | 1 |
Sider (fra-til) | 61-66 |
Antal sider | 6 |
ISSN | 0014-5793 |
DOI | |
Status | Udgivet - 25 sep. 1998 |
Bibliografisk note
Funding Information:The skillful technical assistance of Rikke Grønholt, Alice Lieth and Lisa Swanberg is gratefully acknowledged. The study was supported by the National Institutes of Health CMASIB Training Grant (K.A.L.); the P. Carl Petersens Foundation (L.F.H.); the Danish MRC (J.F.R. and L.F.H.); the Danish Biotechnology Center for Cellular Communication (J.F.R.); the University of Michigan Peptide Center (L.C.S.) and the National Institutes of Health (L.C.S.). L.C.S. and J.F.R. are both senior authors.