title: The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits.
abstract: 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.
authors.affiliation: Section on Cellular Neurobiology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Niamh X
authors.initials: NX
authors.lastname: Cawley
authors.forename: Jiechun
authors.initials: J
authors.lastname: Zhou
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Hill
authors.forename: Daniel
authors.initials: D
authors.lastname: Abebe
authors.forename: Sylvie
authors.initials: S
authors.lastname: Romboz
authors.forename: Tulin
authors.initials: T
authors.lastname: Yanik
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Y Peng
authors.initials: YP
authors.lastname: Loh
mesh_terms: D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001522:Behavior, Animal; D049628:Body Size / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D002153:Calorimetry, Indirect; D043423:Carboxypeptidase H / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D004326:Drinking; D004435:Eating; D004700:Endocrine System Diseases / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D005260:Female; D005298:Fertility; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000097:blood; D009765:Obesity / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D010641:Phenotype; D011384:Proinsulin / Q000097:blood; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D020738:Leptin; D009419:Nerve Tissue Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D011384:Proinsulin; D043423:Carboxypeptidase H