TY - JOUR
T1 - Deficits in reproduction and pro-gonadotropin-releasing hormone processing in male Cpefat mice
AU - Srinivasan, Sudha
AU - Bunch, Donna O.
AU - Feng, Yun
AU - Rodriguiz, Ramona M.
AU - Li, Min
AU - Ravenell, Roneka L.
AU - Luo, Guo X.
AU - Arimura, Akira
AU - Fricker, Lloyd D.
AU - Eddy, Edward M.
AU - Wetsel, William C.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/4
Y1 - 2004/4
N2 - Cpefat/fat mice are obese, diabetic, and infertile. These animals have a point mutation in carboxypeptidase E (CPE), an exopeptidase that removes C-terminal basic amino acids from peptide intermediates. The mutation renders the enzyme unstable, and it is rapidly degraded. Although the infertility of Cpefat/fat mice has not been systematically investigated, it is thought to be due to a deficit in GnRH processing. We have evaluated this hypothesis and found hypothalamic GnRH levels to be reduced by 65-78% and concentrations of pro-GnRH and C-terminal-extended intermediates to be high. Basal serum gonadotropin contents are similar among wild-type, heterozygous, and homozygous mice. Testis morphology and function are abnormal in older obese Cpefat/fat mice. Matings between homozygous mutants yield a 5% pregnancy rate. By comparison, when 50-d-old Cpefat/fat males are paired with heterozygous females, rates increase to 43%, and they rapidly decrease to negligible levels by 120 d. As fertility declines without accompanying changes in the hypothalamic-pituitary-gonadal axis and before obesity is evident, reproduction is more complex than originally thought. This suspicion is confirmed in 90-d-old Cpefat/fat males, who readily interact with females, but rarely mount and fail to show intromission or ejaculation behaviors. Together, these findings show that CPE is a key enzyme for pro-GnRH processing in vivo; however, the reproductive deficits in Cpe fat/fat males appear to be due primarily to abnormal sexual behavior.
AB - Cpefat/fat mice are obese, diabetic, and infertile. These animals have a point mutation in carboxypeptidase E (CPE), an exopeptidase that removes C-terminal basic amino acids from peptide intermediates. The mutation renders the enzyme unstable, and it is rapidly degraded. Although the infertility of Cpefat/fat mice has not been systematically investigated, it is thought to be due to a deficit in GnRH processing. We have evaluated this hypothesis and found hypothalamic GnRH levels to be reduced by 65-78% and concentrations of pro-GnRH and C-terminal-extended intermediates to be high. Basal serum gonadotropin contents are similar among wild-type, heterozygous, and homozygous mice. Testis morphology and function are abnormal in older obese Cpefat/fat mice. Matings between homozygous mutants yield a 5% pregnancy rate. By comparison, when 50-d-old Cpefat/fat males are paired with heterozygous females, rates increase to 43%, and they rapidly decrease to negligible levels by 120 d. As fertility declines without accompanying changes in the hypothalamic-pituitary-gonadal axis and before obesity is evident, reproduction is more complex than originally thought. This suspicion is confirmed in 90-d-old Cpefat/fat males, who readily interact with females, but rarely mount and fail to show intromission or ejaculation behaviors. Together, these findings show that CPE is a key enzyme for pro-GnRH processing in vivo; however, the reproductive deficits in Cpe fat/fat males appear to be due primarily to abnormal sexual behavior.
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U2 - 10.1210/en.2003-1442
DO - 10.1210/en.2003-1442
M3 - Article
C2 - 14715715
AN - SCOPUS:12144286825
SN - 0013-7227
VL - 145
SP - 2023
EP - 2034
JO - Endocrinology
JF - Endocrinology
IS - 4
ER -