Deficits in Reproduction and Pro-Gonadotropin-Releasing Hormone Processing in Male Cpefat Mice

S Srinivasan, DO Bunch, Y Feng, RM Rodriguiz… - …, 2004 - academic.oup.com
S Srinivasan, DO Bunch, Y Feng, RM Rodriguiz, M Li, RL Ravenell, GX Luo, A Arimura…
Endocrinology, 2004academic.oup.com
Cpe fat/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 Cpe fat/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 …
Abstract
Cpe fat/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 Cpefat/fat males appear to be due primarily to abnormal sexual behavior.
Oxford University Press