A Leptin Receptor Mutation Which Impairs Fertility in Ewes Causes Delayed Puberty in Male and Female Mice

TL;DR

A mutation in the leptin receptor delays puberty in mice and affects body weight, but does not prevent adult fertility.

Contribution

The study shows the conserved role of a leptin receptor region in puberty and adiposity across species.

Findings

The A63C mutation caused delayed puberty in both male and female mice.

The A63C mutation increased body weight and adiposity in female mice.

Leptin signaling pathways remained largely intact despite the mutations.

Abstract

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.

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