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Deficits in Reproduction and Pro-Gonadotropin-Releasing Hormone Processing in Male Cpe^fat Mice

Departments of Psychiatry and Behavioral Sciences, Medicine (Endocrinology), and Cell Biology and Mouse Behavioral and Neuroendocrine Analysis Core Facility (S.S., R.M.R., R.L.R., G.X.L., W.C.W.), Duke University Medical Center, Durham, North Carolina 27710; Department of Molecular Pharmacology, Albert Einstein College of Medicine (Y.F., L.D.F.), Bronx, New York 10461; Gamete Biology Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences (D.O.B., E.M.E.), Research Triangle Park, North Carolina 27709; and U.S.-Japan Biomedical Research Laboratories, Tulane University Herbert Center (M.L., A.A.), Belle Chase, Louisiana 70037

Address all correspondence and requests for reprints to: Dr. William C. Wetsel, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3497, 028 CARL Building, Durham, North Carolina 27710. E-mail: wetse001{at}mc.duke.edu.

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.

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