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 deve lopment 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) Not. Genet. 10, 135-142), Examination of the lev el of neuropeptides in these mice showed a decrease in mature bioactive pep tides as a result of a decrease in both carboxypeptidase and prohormone con vertase activities. A defect in CPE is not expected to affect endoproteolyt ic processing. In this report we have addressed the mechanism of this unexp ected finding by directly examining the expression of the major precursor p rocessing endoproteases, prohormone convertases. PC1 and PC2 in Cpe(fat) mi ce. 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 bee n implicated in the generation of neuroendocrine peptides dynorphin A-17, b eta -endorphin, and (alpha- melanocyte-stimulating hormone) involved in the control of feeding behavior and body weight, we compared the levels of the se peptides in Cpe(fat) and wild type animals. We found a marked increase i n 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 proces sed beta -endorphhin. These results suggest that the impairment in the leve l of these and other peptides involved in body weight regulation is mainly due to an alteration in carboxypeptidase and prohormone convertase activiti es and that this may lead to the development of obesity in these animals.