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.