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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.<\/jats:p>","DOI":"10.1210\/endocr\/bqaf058","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T19:52:18Z","timestamp":1743191538000},"source":"Crossref","is-referenced-by-count":1,"title":["A Leptin Receptor Mutation Which Impairs Fertility in Ewes Causes Delayed Puberty in Male and Female Mice"],"prefix":"10.1210","volume":"166","author":[{"given":"Rebecca A","family":"Lord","sequence":"first","affiliation":[{"name":"Centre for Neuroendocrinology, and Department of Anatomy, University of Otago School of Biomedical Sciences , Dunedin 9016 ,","place":["New Zealand"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan A","family":"Inglis","sequence":"additional","affiliation":[{"name":"Centre 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