Department of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, MO, USA.
Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA.
Biol Reprod. 2022 Aug 9;107(2):546-556. doi: 10.1093/biolre/ioac062.
Leptin is required for fertility, including initiation of estrous cycles. It is therefore challenging to assess the role of leptin signaling during pregnancy. Although 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.
瘦素对于生育能力是必需的，包括发情周期的启动。因此，评估妊娠期间瘦素信号的作用具有挑战性。尽管神经元特异性转基因方法表明中枢神经系统中的瘦素信号最重要，但在子宫内用药物抑制瘦素或在妊娠期间全身替代瘦素的实验表明，生殖道中的瘦素信号可能是必需的。在这里，使用孕激素受体驱动的 Cre 重组酶的条件性瘦素受体敲除 (Lepr cKO) 来检查妊娠期间瘦素信号的重要性。Lepr cKO 小鼠的子宫或宫颈中的瘦素受体几乎不存在，黄体中的瘦素受体水平略有降低。发情周期和孕酮浓度不受 Lepr cKO 的影响。妊娠第 6.5 和 17.5 天，初产对照和 Lepr cKO 母鼠的活胚胎数量没有差异，尽管胚胎与黄体的比例略有降低，表明子宫瘦素受体信号对于胚胎着床不是必需的。Lepr cKO 母鼠的胎盘重量和结构正常。然而，经过四轮繁殖，Lepr cKO 小鼠的活产仔数比对照组少 22%，并且在第四轮繁殖时从配对到分娩所需的时间更长。Lepr cKO 分娩中有 33%发生难产或死产，而对照组则没有，并且蜷缩后每个幼崽的分娩时间明显增加。因此，生殖道中的瘦素受体信号对于正常分娩是必需的。
