Deficits in reproduction and pro-gonadotropin-releasing hormone processing in male Cpefat mice.

Journal Article

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 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 Cpe(fat/fat) mice. Matings between homozygous mutants yield a 5% pregnancy rate. By comparison, when 50-d-old Cpe(fat/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 Cpe(fat/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.

Full Text

Duke Authors

Cited Authors

  • Srinivasan, S; Bunch, DO; Feng, Y; Rodriguiz, RM; Li, M; Ravenell, RL; Luo, GX; Arimura, A; Fricker, LD; Eddy, EM; Wetsel, WC

Published Date

  • April 2004

Published In

Volume / Issue

  • 145 / 4

Start / End Page

  • 2023 - 2034

PubMed ID

  • 14715715

International Standard Serial Number (ISSN)

  • 0013-7227

Digital Object Identifier (DOI)

  • 10.1210/en.2003-1442

Language

  • eng

Conference Location

  • United States