Lord Rebecca A, Inglis Megan A, Juengel Jennifer L, Anderson Greg M
Centre for Neuroendocrinology, and Department of Anatomy, University of Otago School of Biomedical Sciences, Dunedin 9016, New Zealand.
Agricultural Systems and Reproduction, AgResearch Ltd, Invermay Agricultural Centre, Mosgiel 9092, New Zealand.
Endocrinology. 2025 Mar 24;166(5). doi: 10.1210/endocr/bqaf058.
Reproductive function is tightly linked to nutritional status due to its high energetic demands. Leptin, a key adipose tissue-derived hormone signalling energy reserves to the brain, integrates metabolic status with the hypothalamic-pituitary-gonadal axis to ensure reproductive function is maintained or suppressed appropriately. Mutations in leptin or its receptor (LepR) are known to cause infertility and obesity in mice. In Davisdale ewes, 2 naturally occurring LepR mutations (R62C and P1019S) were associated with delayed puberty and subfertility, but their effects in males or in other species remain to be determined. This study examined the impact of analogous LepR mutations (A63C and P1018S) in mice using CRISPR-Cas9 gene editing. Puberty onset, adult fertility, and metabolic phenotypes were assessed in wild-type, heterozygous, and homozygous mutant mice. The A63C mutation, located in the extracellular domain of the receptor, resulted in increased body weight and adiposity in females, along with delays in puberty onset in both sexes. Despite these delays, adult reproductive function was maintained. Immunohistochemical analysis revealed no detectable reductions in leptin-induced pSTAT3, pERK1/2, or pmTOR signalling in the hypothalamic arcuate nucleus in either mutant line, indicating these pathways remain largely intact. These findings demonstrate the conserved importance of this region of the leptin receptor for puberty onset and adiposity across species, but also the resilience of leptin signalling in preserving reproductive function despite genetic variation.
由于生殖功能对能量需求较高，其与营养状况紧密相关。瘦素是一种由脂肪组织分泌的关键激素，可向大脑传递能量储备信号，它将代谢状态与下丘脑 - 垂体 - 性腺轴整合起来，以确保生殖功能得到适当维持或抑制。已知瘦素或其受体（LepR）的突变会导致小鼠不育和肥胖。在戴维斯代尔母羊中，两种自然发生的LepR突变（R62C和P1019S）与青春期延迟和生育力低下有关，但它们对雄性或其他物种的影响仍有待确定。本研究使用CRISPR - Cas9基因编辑技术，研究了小鼠中类似的LepR突变（A63C和P1018S）的影响。对野生型、杂合子和纯合子突变小鼠的青春期启动、成年生育力和代谢表型进行了评估。位于受体细胞外结构域的A63C突变导致雌性体重和脂肪量增加，同时两性青春期启动延迟。尽管有这些延迟，但成年生殖功能得以维持。免疫组织化学分析显示，在任一突变系的下丘脑弓状核中，瘦素诱导的pSTAT3、pERK1/2或pmTOR信号均未检测到降低，表明这些信号通路在很大程度上保持完整。这些发现证明了瘦素受体这一区域在跨物种青春期启动和肥胖方面的重要性具有保守性，同时也表明尽管存在基因变异，但瘦素信号在维持生殖功能方面具有弹性。
