Research Projects

The reproductive function requires multiple central and peripheral cues that ensure the perpetuation of the species (Prashar et al., 2023). Gonadotropin-releasing hormone (GnRH) conveys all these regulatory cues to the Hypothalamic-pituitary-gonadal axis (HPG axis) (Prashar et al., 2023). The rising prevalence of metabolic disorders involving excess energy stores, including obesity, has been linked with a rise in the incidence of precocious puberty, abnormal menstrual cycles (Vanacker, 2015), polycystic ovary syndrome (PCOS) and infertility. Given this alarming increase in metabolic disorders and their association with conditions such as infertility, a great deal of research has been devoted to elucidating the mechanisms underlying these disorders and their relationship to the neuroendocrine reproductive axis (Vanacker, 2015). GnRH neurons do not have receptors for oestrogen, progesterone, or androgens, and thus the disrupted feedback is hypothesized to occur via upstream neurons. Likely candidates for these upstream regulators of GnRH neuronal pulsatility are Kisspeptin, Neurokinin B (NKB), and Dynorphin neurons (termed KNDy neurons) (Walters et al., 2018). Two populations of kisspeptin synthesizing neurons are present in the rodent's hypothalamus, in the ARC and AVPV region (Kinoshita et al., 2005; Smith et al., 2006) that mainly project to GnRH neurons. The ARC, kisspeptin neurons co-express NKB and dynorphin, also named KNDy neurons (Goodman et al., 2007; Lehman et al., 2010). The ARC (KNDy neurons) and AVPV region kisspeptin neurons act as a “GnRH pulse generator” and “GnRH surge generator,” respectively (Herbison, 2016, 2018; Nagae et al., 2021; Navarro et al., 2009; Uenoyama et al., 2021). Growing insight into the neuroendocrine dysfunction underpinning the heightened GnRH pulsatility seen in PCOS has led to research on the use of pharmaceutical agents that specifically target the activity of these KNDy neurons to attenuate symptoms of PCOS. PCOS phenomenon is also associated with high plasma concentration AMH. In females, AMH is secreted by the granulosa cells of ovarian follicles. Androgens in turn inhibit the action of AMH, and circulating androgen levels during fetal development are correlated with AMH concentrations during adolescence. However, while this pathway explains in part the androgenization seen in PCOS, it does not directly address the question of increased GnRH neuronal pulsatility w.r.t. AMH, KNDy and NO. On the other hand leptin, an adipocyte-derived hormone secreted in proportion to body fat mass, has been linked to the regulation of both metabolic and reproductive function (Vanacker, 2015). Chronically elevated leptin levels, both a characteristic of obesity and a condition known to accelerate puberty and prolong the menstrual cycle, may indeed account for the increased prevalence of reproductive impairment in obese patients (Vanacker, 2015). In this research proposal, I am focusing on how food-fat-brain axis influences sexual maturation and fertility, with a specific attention paid to the select population of hypothalamic neurons synthesizing NO that may play a key role both in the central control of reproduction and of systemic energy balance, is thus of high significance and addresses an important topic. We will use multi-omics approaches like in silico, in vitro and PAMH mouse model and human samples to uncover the molecular mechanisms that underlie in the metabolic diseases like obesity and PCOS. This project will investigate the molecular mechanisms and will also provide new information that will be of great interest for the development of new diagnostic and/or therapeutic tools that are urgently needed to treat obesity and infertility related disorder like PCOS. Finally, the data gained from the proposed research project are potentially of important interest for public health and may help find interventions to treat infertility, obesity and associated diseases like PCOS.