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

Sudha Srinivasan, Donna O. Bunch, Yun Feng, Ramona M. Rodriguiz, Min Li, Roneka L. Ravenell, Guo X. Luo, Akira Arimura, Lloyd D. Fricker, Edward M. Eddy, William C. Wetsel

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2023-2034
Number of pages12
JournalEndocrinology
Volume145
Issue number4
DOIs
Publication statusPublished - Apr 1 2004

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ASJC Scopus subject areas

  • Endocrinology

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Srinivasan, S., Bunch, D. O., Feng, Y., Rodriguiz, R. M., Li, M., Ravenell, R. L., ... Wetsel, W. C. (2004). Deficits in reproduction and pro-gonadotropin-releasing hormone processing in male Cpefat mice. Endocrinology, 145(4), 2023-2034. https://doi.org/10.1210/en.2003-1442