How do estrogens orchestrate fertility and energy homeostasis in the central nervous system: mechanistic insights in the membrane and nuclear effects of the Estrogen Receptor alpha (ERalpha) – BENEFIT_Ukraine

The obesity epidemic continues unabated and currently available pharmacological treatments are not sufficiently effective. The consistent worldwide disparity in prevalence of severe obesity strongly suggests that biological factors, i.e. physiological sex differences, in particular sex hormones contribute. Estrogens, and particularly 17ß-estradiol (E2), play a major role in reproduction but is also involved in the control of food intake and energy homeostasis. This coupling between fertility and energy homeostasis probably insures that fertility only occurs if the metabolic environment is favorable. Indeed, deficiency in mice and also in humans of the Estrogen Receptor ERa, induces not only infertility, but also metabolic complications (obesity and insulin resistance). These fine regulations between reproduction and energy homeostasis appear to operate in the hypothalamus, and in particular in the median eminence (ME), where axon terminals of gonadotropin releasing hormone (GnRH) neurons reside and control gonadotropin hormones (LH and FSH) release in a specific time window during the ovarian cycle through the synthesis of E2 by the ovaries through the feed-forward mechanism at the hypothalamus-pituitary ovarian axis. In the hypothalamus, trafficking of molecules between the peripheral circulation and the central nervous system (CNS) is indeed restricted by regulated interfaces. The blood-cerebrospinal-fluid (CSF) barrier is one of these interfaces, composed of microvessels and of tanycytes, a specialized glial cell lining the wall of third ventricle in the median eminence. These tanycytes appear to act as the linchpins of these processes by dynamically controlling the secretion of neuropeptides into the portal vasculature by hypothalamic neurons and regulating blood-brain and blood-cerebrospinal fluid exchanges, both processes that depend on the ability of these cells to adapt their morphology to the physiological state of the individual.

The general aim of BENEFIT will thus be to determine how estrogens in this blood-CSF barrier (tanycytes and fenestrated vessels) control the access of blood-borne metabolic signals to the hypothalamic structures controlling food intake/energy homeostasis and how they act to orchestrate the neuroglial plasticity to control pulsatile GnRH release, which is important for fertility and to prevent the polycystic syndrome. ERa can act through both nuclear and membrane actions, and genetically modified mouse models with loss of function of membrane and nuclear ERa were developed in the consortium.

The specific aims of the proposal are:
WP1-To determine the effect of the ovarian cycle on changes in the tanycytic blood-CSF barrier and food intake, and determine the putative role of VEGF-A in this process, using infusion of TAT-Cre on the third ventricle of VEGFA-Lox/Lox mice.
WP2-To investigate the role of ERa expression in tanycytes in the control of energy homeostasis and fertility using ERaLoxP/loxPmice and Tat-Cre infusion in the third ventricle (food intake, estrous cyclicity, sensitivity to HFD)
WP3-To explore the respective roles of nuclear and membrane ERa of the gonadotropic axis in fertility and in the estrogen-mediated regulation of GnRH neurovascular junction
WP4-To study how HFD-induced obesity impacts the ovary phenotype (polycystic syndrome) of mice deficient for nuclear or membrane actions of ERa and the changes in the neurovascular junction and metabolism.
WP5-To analyze the polymorphism and potential mutated forms of the ERa gene in a cohort of women with polycystic ovary syndrome.

This work will provide novel insights to understand: i) the cause of selected forms of metabolic alterations in women and ii) the central control of energy homeostasis by estrogens to reduce the metabolic syndrome and to treat causes of infertility or at least at reducing its complications.