Deficits in reproduction and pro-gonadotropin-releasing hormone processing in male Cpefat mice.
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.
Srinivasan
Sudha
S
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA.
Bunch
Donna O
DO
Feng
Yun
Y
Rodriguiz
Ramona M
RM
Li
Min
M
Ravenell
Roneka L
RL
Luo
Guo X
GX
Arimura
Akira
A
Fricker
Lloyd D
LD
Eddy
Edward M
EM
Wetsel
William C
WC
D000818:Animals; D043423:Carboxypeptidase H / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics; D005260:Female; D005298:Fertility; D005835:Genitalia / Q000473:pathology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006720:Homozygote; D007031:Hypothalamus / Q000378:metabolism; D007246:Infertility / Q000235:genetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009765:Obesity / Q000235:genetics; D009929:Organ Size; D010903:Pituitary Gland, Anterior / Q000503:physiopathology; D011247:Pregnancy; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012098:Reproduction / Q000235:genetics*; D012726:Sexual Behavior, Animal
D011498:Protein Precursors; C050866:progonadoliberin I; D007987:Gonadotropin-Releasing Hormone; D043423:Carboxypeptidase H