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The Carboxypeptidase E Knockout Mouse Exhibits Endocrinological and Behavioral Deficits

Section on Cellular Neurobiology (N.X.C., J.M.H., D.A., T.Y., Y.P.L.), Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Departments of Psychiatry and Behavioral Sciences (J.Z., R.M.R., W.C.W.), Cell Biology and Medicine (Endocrinology), Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, North Carolina 27710; and Xenogen Biosciences Corporation (S.R.), Cranbury, New Jersey 08512

Address all correspondence and requests for reprints to: Dr. Y. Peng Loh, Building 49, Room 5A22, 49 Convent Drive, MSC 4480, National Institutes of Health, Bethesda, Maryland 20892. E-mail: lohp{at}mail.nih.gov.

A carboxypeptidase E (CPE) knockout (KO) mouse was generated by deletion of exons 4 and 5 from the CPE gene, and its phenotype was characterized. KO mice became obese by 10–12 wk of age and reached 60–80 g by 40 wk. At this age, body fat content was more than double that in the wild-type (WT) controls. The null animals consumed more food overall, were less physically active during the light phase of the light-dark cycle, and burned fewer calories as fat than WT littermates. Fasting levels of glucose and insulin-like immunoreactivity in plasma were elevated in both male and female KO mice at approximately 20 wk; males recovered fully and females partially from this state by 32 wk. At this time, insulin-like immunoreactivity in the plasma, identified as proinsulin, was 50–100 times higher than that of the WT animals. The KO mice showed impaired glucose clearance and were insulin resistant. High levels of leptin and no circulating fully processed cocaine- and amphetamine-related transcript, a peptide that is responsive to leptin-induced feedback inhibition of feeding, were found in serum. The KO mice were subfertile and showed deficits in GnRH processing in the hypothalamus. Behavioral analyses revealed that KO animals showed diminished reactivity to stimuli and had reduced muscle strength and coordination, as well as visual placing and toe-pinch reflexes. These data demonstrate that CPE KO mice display a wide range of neural and endocrine abnormalities and suggest that CPE may have additional physiological roles beyond those ascribed to peptide processing and sorting of prohormones in cells.

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