OR13-05 Neuronal CRTC1 modulates pubertal timing and body weight in mice

Abstract Disclosure: G.M. Anderson: None. A.S. Rajan: None. R.A. Lord: None. M.A. Inglis: None. C. Decourt: None. Correct timing of puberty involves coordination of multiple genes, hormones and central nervous system circuits, culminating in the release of hypothalamic GnRH neurons from inhibitory pre-pubertal influences and their activation by stimulatory inputs (most notably, by the neuropeptide kisspeptin). Human puberty occurs over a very variable (∼5 year) time-frame, and a notable decline in pubertal age has occurred over the last century, particularly in girls. A key hormonal signal for puberty onset is increasing levels of leptin, secreted by adipose tissue, as fat stores mature towards adult levels. Leptin signals via it’s membrane receptor via multiple intracellular pathways, including the canonical Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway which is required for normal puberty onset, subsequent fertility and metabolic regulation. The aim of this project is to test if other signalling pathways used by leptin are also involved in these processes. We used Cre-loxP transgenic mice to delete the following leptin receptor signalling molecules from Cam kinase II alpha-expressing brain neurons: CREB-regulated transcription coactivator 1 (CRTC1), extracellular signal-regulated kinase 2 (ERK2/MAPK1) or mammalian target of rapamycin (mTOR). Puberty onset, reproductive activity and metabolic function were assessed in knockouts and littermate controls not expressing Cre (n=6-12/group). CRTC1 knockout females showed a small delay in vaginal opening (31±0.3 days vs. 30±0.3 days in controls, p=0.014) and first estrus (33±0.2 days vs. 31±0.2 days, p=0.001), as well as a large increase in estrous cycle length (9.4±1.6 days vs. 4. 6±0.2 days, p=0.001). No significant difference was observed in date of male puberty (preputial separation). Male and female knockout mice were fertile, but exhibited significantly higher body weight compared to controls from weeks 4-10 of age (p<0.05), along with increased fat mass (p=0.0001). In contrast, mice with ERK2 or mTOR deletion showed no reproductive or metabolic deficit5s compared to controls. These data show that neuronal CRTC1 (but not ERK2 or mTOR) modulates puberty timing and reproductive activity in female mice, and adiposity in both sexes. It was previously shown that CRTC1 drives gene expression of kisspeptin, which may provide a mechanism for the reproductive deficits observed in CRTC1 knockout females. This link to kisspeptin expression is currently being investigated in our lab. Presentation: Sunday, July 13, 2025