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.

An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers

“…An approximately 55-kDa membrane form of CPE anchored to cholesterol/sphingolipid-rich microdomains at the trans-Golgi network (TGN) functions as a receptor for sorting prohormones into the regulated secretory pathway granules for secretion (9,10). Hence, mice with Cpe mutations that lack CPE, and Cpe-knockout mice, have many pathophysiological conditions, such as diabetes, infertility, obesity, low bone mineral density, and deficits in learning and memory (11)(12)(13)(14).…”

Interaction between secretogranin III and carboxypeptidase E facilitates prohormone sorting within secretory granules

“…shown by the presence of unprocessed prohormone intermediates such as prodynorphin intermediates and ␣-melanocyte-stimulating hormone (␣MSH) precursors (Berman et al, 2001), pro-thyrotropin-releasing hormone intermediates (Nillni et al, 2002), procholecystokinin intermediates (Lacourse et al, 1998), and proinsulin and cocain-and amphetamine-related transcript (CART) precursors (Cawley et al, 2004) in Cpe fat mice and CPE-knockout mice. Among these hormones, inefficient production of mature ␣MSH and CART is suggested to enhance food intake and lead to adult-onset obesity in the Cpe fat mouse and CPE-knockout mouse (Zimmermann-Belsing andFeldt-Rasmussen, 2004: Cawley et al, 2004).…”

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

“…Notably, the fat/fat mice show the phenotype of obesity, indicating participation of neuropeptides in the fat/fat condition. Furthermore, knockout of the CPE gene results in endocrinological behavioral deficits, including more food intake, elevation of plasma glucose during fasting, and insulin resistance (75). Such findings implicate CPE in physiological roles of prohormone processing in physiological conditions.…”

“…The exopeptidase carboxypeptidase E has been examined in vivo as an inactive mutant CPE of the Cpefat/fat mice (73,74) and in CPE gene knockout mice (75). Analyses of peptides representing CPE substrates demonstrated their accumulation in the Cpefat/fat mice.…”