Impaired prohormone convertases in Cpe(fat)/Cpe(fat) mice.
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 Cpe(fat) 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 Cpe(fat) 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.
Berman
Y
Y
Department of Pharmacology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016, USA. bermay01@med.nyu.edu
Mzhavia
N
N
Polonskaia
A
A
Devi
L A
LA
D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight; D001921:Brain / Q000201:enzymology*; D043423:Carboxypeptidase H; D002268:Carboxypeptidases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D004723:Endorphins / Q000737:chemistry / Q000494:pharmacology; D004745:Enkephalins / Q000378:metabolism; D005247:Feeding Behavior; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D010902:Pituitary Gland / Q000201:enzymology*; D017354:Point Mutation; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D043484:Proprotein Convertases; D011498:Protein Precursors / Q000378:metabolism; D012016:Reference Values; D013381:Subtilisins / Q000235:genetics / Q000378:metabolism*
D004723:Endorphins; D004745:Enkephalins; D010446:Peptide Fragments; D011498:Protein Precursors; D011333:Pro-Opiomelanocortin; C033660:preproenkephalin; D002268:Carboxypeptidases; D043423:Carboxypeptidase H; D043484:Proprotein Convertases; D013381:Subtilisins; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1; D045706:Proprotein Convertase 2; D016282:Aspartic Acid Endopeptidases