Abstract
Puberty and fertility are regulated by intricate neuroendocrine systems, with the hypothalamic-pituitary-gonadal (HPG) axis playing a crucial role. Leptin, a hormone secreted by adipose tissue, is a key player in this regulatory network which influences appetite, energy expenditure, and metabolic balance. Although leptin's impact on puberty, reproduction, and fertility has been recognized, the precise mechanisms through which it exerts these effects remain poorly understood.
Recent research has highlighted signal transducer and activator of transcription 3 (STAT3) as a crucial component in the regulation of various reproductive processes including puberty onset and fertility, particularly through its role in the leptin signaling cascade. However, emerging evidence suggests that STAT3 is not the sole player. The complexity of leptin signaling involves multiple interacting molecules, and recent studies have shifted attention to other significant players.
CREB-regulated transcription coactivator 1 (CRTC1), a less well-known leptin signaling molecule, has been identified as a key regulator for gene expression of kisspeptin, a neuropeptide known to be integral to the reproductive axis. Kisspeptin's role in initiating puberty and regulating fertility underscores the importance of understanding its regulatory mechanisms. This project aims to explore the role of CRTC1 in reproductive signaling and determine how disruptions in CRTC1 affects puberty onset and fertility.
In this study, I investigated the impact of CRTC1 knockout specifically in brain neurons on puberty onset, metabolic function and fertility in male and female mice. Knockout females showed a delayed vaginal opening (31±0.3 days vs. 30±0.3 days in controls, p=0.0143) and first estrus (33±0.2 days vs. 31±0.2 days, p=0.0013), with significant increases in estrous cycle length (9.42±1.6 days vs. 4.56±0.2 days, p=0.001). For male puberty, no significant differences were observed in date of preputial separation. Male and female knockout mice 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) and reduced lean mass (p=0.0042). Data from insulin resistance and fertility assessments are currently being analysed.
These findings suggest that CRTC1 knockout may delay puberty in female mice and influence body weight in both sexes. Understanding how CRTC1 influences leptin signalling and its impact on metabolic health and puberty contributes to the understanding of the molecular mechanisms underlying reproductive development. This research highlights the need for further investigation into the exact pathways leptin regulates fertility, with potential implications for developing targeted diagnostics and therapies for reproductive disorders in humans.