Folliculogenesis is impaired and granulosa cell apoptosis is increased in leptin-deficient mice.

Leptin purportedly plays an important role in pubertal development in a number of mammalian species. Adult leptin-deficient (ob/ob) female mice are infertile, but the mechanisms responsible for the reproductive failure have not been fully elucidated. The major objective of the current study was to assess the effects of a leptin deficiency on ovarian folliculogenesis and apoptosis. Beginning at 4 wk of age, control (n = 8) and ob/ob (n = 7) mice were weighed and examined daily for vaginal opening. After 3 wk the mice were killed, and the reproductive organs were weighed. Ovaries were paraffin-embedded for hematoxylin and eosin histology, TUNEL assay, and immunohistochemistry for Fas, Fas ligand (FasL), and proliferating cell nuclear antigen (PCNA). Vaginal opening was delayed, uteri were smaller, and the number of primordial follicles and total number of ovarian follicles were subnormal in ob/ob animals. Leptin-deficient animals also had a higher number of atretic follicles than controls. Granulosa cells (predominantly in preantral and early antral follicles) of ob/ob mice exhibited increased apoptotic activity as documented by TUNEL assay and elevated expression of the apoptotic markers Fas and FasL, compared with that in control animals. Ovarian expression of PCNA, a marker of DNA replication, repair, or both, did not differ between ob/ob and control mice. The data suggest that a leptin deficiency in mice is associated with impaired folliculogenesis, which results in increased follicular atresia. This impairment may be one of the causative components of infertility in leptin-deficient animals.