The adipose-derived hormone leptin plays an integral role in normal reproductive function. The canonical Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) is the most extensively studied leptin receptor (LepR) pathway. It’s well known that neural STAT3 deletion results in hyperphagia and obesity, but its reproductive role is less clear.
Previous data suggests STAT3-signalling, while critical for leptin’s effects on body-weight, may be unnecessary for reproduction [1]. Since reproductive capacity of C57BL/6 mice is unaffected by metabolic challenges [2], this surprising finding warrants re-evaluation on a more suitable strain. Hence, the aim of this experiment was to determine whether STAT3 knockout (KO) in a DBAJ/2 background, a strain susceptible to reproductive impairments and metabolic challenges, would reveal the requirement for STAT3 in reproductive function.
Transgenic mice with LepR-specific-deletion of STAT3 were generated using Cre-loxP. Reproductive and metabolic effects were explored in two background strains: C57BL/6 and DBAJ/2 (n=6-11 per group). Puberty onset was measured post-weaning by daily visual examination of the genitalia. Reproductive cyclicity (females) and reproductive organ weight (both sexes) were assessed as adults. Metabolic effects were assessed via body and abdominal-fat weight and fasting glucose levels. Additionally, brain tissue was used to assess cellular leptin-responsiveness of STAT3.
Analysis of body weight revealed STAT3 KO females had significantly increased body weight (by 11 weeks [p=0.0093]) compared to controls (unpaired t-test). STAT3 KO males had normal bodyweight regulation. All STAT3 KO mice exhibited unchanged puberty onset, estrous cyclicity, and reproductive organ weight compared to control mice.
These data support the conclusion that leptin’s actions on puberty timing and reproductive function are independent of STAT3. Another possibility we’re investigating is that LepR-Cre is not powerful enough to drive complete STAT3 excision. Nevertheless, the role of different LepR signalling-pathways has become particularly relevant to the multiple functions of leptin.