Conditional knockout of leptin receptor in the female reproductive tract reduces fertility due to parturition defects in mice

Abstract

Leptin is required for fertility, including initiation of estrous cycles. It is therefore challenging to assess the role of leptin signaling during pregnancy. While neuron-specific transgene approaches suggest that leptin signaling in the central nervous system is most important, experiments with pharmacologic inhibition of leptin in the uterus or global replacement of leptin during pregnancy suggest leptin signaling in the reproductive tract may be required. Here, conditional leptin receptor knockout (Lepr cKO) with a progesterone receptor-driven Cre recombinase was used to examine the importance of leptin signaling in pregnancy. Lepr cKO mice have almost no leptin receptor in uterus or cervix, and slightly reduced leptin receptor levels in corpus luteum. Estrous cycles and progesterone concentrations were not affected by Lepr cKO. Numbers of viable embryos did not differ between primiparous control and Lepr cKO dams on days 6.5 and 17.5 of pregnancy, despite a slight reduction in the ratio of embryos to corpora lutea, showing that uterine leptin receptor signaling is not required for embryo implantation. Placentas of Lepr cKO dams had normal weight and structure. However, over four parities, Lepr cKO mice produced 22% fewer live pups than controls, and took more time from pairing to delivery by their fourth parity. Abnormal birth outcomes of either dystocia or dead pups occurred in 33% of Lepr cKO deliveries but zero control deliveries, and the average time to deliver each pup after crouching was significantly increased. Thus, leptin receptor signaling in the reproductive tract is required for normal labor and delivery. Summary sentence. Mice lacking leptin receptor in the reproductive tract produce fewer live pups and have more adverse labor outcomes than controls, but normal numbers of embryos near term, showing that leptin receptor signaling is required for normal parturition.

The uterine secretome initiates growth of gynecologic tissues in ectopic locations

“…Primary antibody recombinant anti-Fox2a antibody (ab108422) and secondary goat anti-rabbit IgG H&L HRP conjugated (ab6721) were obtained from abcam and used according to manufacturer's instructions. DAB Substrate kit (abcam) was used according to manufacturer's instructions for visualization, hematoxylin was used to counterstain nuclei as we previously described [30].…”