Abstract
Leptin, an adipose-derived hormone, is required for fertility. The signal transducer and activator of transcription 3 (STAT3) pathway is the most well-characterised leptin signalling pathway. Neural STAT3 deletion is known to cause obesity, however its reproductive role is less-understood. We investigated whether STAT3 signalling is required for reproduction. We also tested the role of extracellular signal-regulated kinase 2 (ERK2/MAPK1), an alternative leptin signalling pathway.
Transgenic mice with neuronal STAT3 or ERK2 knockout, with matched controls (n=7-11/group) were created using the Cre-loxP system (CamKinaseIIα-Cre). Puberty onset was observed post-weaning by examining genitalia. Reproductive cyclicity and organ weights were measured in adults. Metabolic effects were evaluated through bodyweight, abdominal fat and fasting glucose measurements. Brain tissue was analysed to assess STAT3 and ERK2 cellular response to leptin. Data is presented as mean ± the standard error of the mean.
STAT3 KO mice showed significantly increased bodyweight by 5-weeks (P<0.001, repeated-measures two-way ANOVA) and abdominal adiposity (KO: 4.1±0.25 g; Control: 0.7±0.10 g, P<0.001, Student’s t-test) compared to controls. Males had a significant 5-day delay in preputial separation (KO: 32.1±2.09 d; Control: 26.8±0.45 d, P<0.01, Student’s t-test). Females exhibited a significant 7-day delay in vaginal opening (KO: 33.0±1.85 d, Control: 26.6±0.37 d, P<0.05, Student’s t-test), a 9-day delay in first estrus (KO: 37.8±1.89 d; Control: 29.4±0.65 d, P<0.01, Student’s t-test) and pronounced acyclicity. STAT3 KO mice had elevated fasting glucose levels (KO: 23.6±2.81 mmol/L; Control: 10.2 mmol/L±0.30 mmol/L, P<0.001, Student’s t-test) and regressed reproductive organs. In contrast, mice with ERK2-KO showed no reproductive or metabolic deficits compared to controls.
These data have prompted re-evaluation of previous conclusions that STAT3 is not necessary for normal reproduction, since these results highlight its importance in reproduction while ERK2 appears less critical. Future experiments will target STAT3 knockout to specific neuronal populations known to be important for reproduction.