Gliotransmission by Prostaglandin E2: A Prerequisite for GnRH Neuronal Function?

Over the past four decades it has become clear that prostaglandin E2 (PGE2), a phospholipid-derived signaling molecule, plays a fundamental role in modulating the gonadotropin-releasing hormone (GnRH) neuroendocrine system and in shaping the hypothalamus. In this review, after a brief historical overview, we highlight studies revealing that PGE2 released by glial cells such as astrocytes and tanycytes is intimately involved in the active control of GnRH neuronal activity and neurosecretion. Recent evidence suggests that hypothalamic astrocytes surrounding GnRH neuronal cell bodies may respond to neuronal activity with an activation of the erbB receptor tyrosine kinase signaling, triggering the release of PGE2 as a chemical transmitter from the glia themselves, and, in turn, leading to the feedback regulation of GnRH neuronal activity. At the GnRH neurohemal junction, in the median eminence of the hypothalamus, PGE2 is released by tanycytes in response to cell–cell signaling initiated by glial cells and vascular endothelial cells. Upon its release, PGE2 causes the retraction of the tanycyte end-feet enwrapping the GnRH nerve terminals, enabling them to approach the adjacent pericapillary space and thus likely facilitating neurohormone diffusion from these nerve terminals into the pituitary portal blood. In view of these new insights, we suggest that synaptically associated astrocytes and perijunctional tanycytes are integral modulatory elements of GnRH neuronal function at the cell soma/dendrite and nerve terminal levels, respectively

MCH regulates SIRT1/FoxO1 and reduces POMC neuronal activity to induce hyperphagia, adiposity and glucose intolerance

Melanin concentrating hormone (MCH) is an important regulator of food intake, glucose metabolism and adiposity. However, the mechanisms mediating these actions remain largely unknown. We used pharmacological and genetic approaches to show that the SIRT1/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity and glucose intolerance. MCH reduces POMC neuronal activity and the SIRT1/FoxO1 pathway regulates the inhibitory effect of MCH on POMC expression. Remarkably, the metabolic actions of MCH are compromised in mice lacking SIRT1 specifically in POMC neurons. Of note, the actions of MCH are independent of AgRP neurons because inhibition of GABA-R in the ARC did not prevent the orexigenic action of MCH; and the hypophagic effect of MCH silencing was maintained after chemogenetic stimulation of AgRP neurons. Central SIRT1 is required for MCH-induced weight gain through its actions on the sympathetic nervous system. The central MCH knockdown causes hypophagia and weight loss in diet-induced obese wild type mice, however, these effects were abolished in mice over-expressing SIRT1 fed a high fat diet. These data reveal the neuronal basis for the effects of MCH on food intake, body weight and glucose metabolism and highlight the relevance of SIRT1/FoxO1 pathway in obesity

The special relationship: glia–neuron interactions in the neuroendocrine hypothalamus

International audienceNatural fluctuations in physiological conditions require adaptive responses involving rapid and reversible structural and functional changes in the hypothalamic neuroendocrine circuits that control homeostasis. Here, we discuss the data that implicate hypothalamic glia in the control of hypothalamic neuroendocrine circuits, specifically neuron-glia interactions in the regulation of neurosecretion as well as neuronal excitability. Mechanistically, the morphological plasticity displayed by distal processes of astrocytes, pituicytes and tanycytes modifies the geometry and diffusion properties of the extracellular space. These changes alter the relationship between glial cells of the hypothalamus and adjacent neuronal elements, especially at specialized intersections such as synapses and neurohaemal junctions. The structural alterations in turn lead to functional plasticity that alters the release and spread of neurotransmitters, neuromodulators and gliotransmitters, as well as the activity of discrete glial signalling pathways that mediate feedback by peripheral signals to the hypothalamus. An understanding of the contributions of these and other non-neuronal cell types to hypothalamic neuroendocrine function is thus critical both to understand physiological processes such as puberty, the maintenance of bodily homeostasis and ageing and to develop novel therapeutic strategies for dysfunctions of these processes, such as infertility and metabolic disorders

Prostaglandin E2 release from astrocytes triggers gonadotropin-releasing hormone (GnRH) neuron firing via EP2 receptor activation.

International audienceAstrocytes in the hypothalamus release prostaglandin E(2) (PGE(2)) in response to cell-cell signaling initiated by neurons and glial cells. Upon release, PGE(2) stimulates the secretion of gonadotropin-releasing hormone (GnRH), the neuropeptide that controls reproduction, from hypothalamic neuroendocrine neurons. Whether this effect on GnRH secretion is accompanied by changes in the firing behavior of these neurons is unknown. Using patch-clamp recording we demonstrate that PGE(2) exerts a dose-dependent postsynaptic excitatory effect on GnRH neurons. These effects are mimicked by an EP2 receptor agonist and attenuated by protein kinase A (PKA) inhibitors. The acute blockade of prostaglandin synthesis by indomethacin (INDO) or the selective inhibition of astrocyte metabolism by fluoroacetate (FA) suppresses the spontaneous firing activity of GnRH neurons in brain slices. Similarly, GnRH neuronal activity is reduced in mice with impaired astrocytic PGE(2) release due to defective erbB signaling in astrocytes. These results indicate that astrocyte-to-neuron communication in the hypothalamus is essential for the activity of GnRH neurons and suggest that PGE(2) acts as a gliotransmitter within the GnRH neurosecretory system

The Versatile Tanycyte: A Hypothalamic Integrator of Reproduction and Energy Metabolism

International audienceThe fertility and survival of an individual rely on the ability of the periphery to promptly, effectively, and reproducibly communicate with brain neural networks that control reproduction, food intake, and energy homeostasis. Tanycytes, a specialized glial cell type lining the wall of the third ventricle in the median eminence of the hypothalamus, appear to act as the linchpin 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. In addition to their barrier properties, tanycytes possess the ability to sense blood glucose levels, and play a fundamental and active role in shuttling circulating metabolic signals to hypothalamic neurons that control food intake. Moreover, accumulating data suggest that, in keeping with their putative descent from radial glial cells, tanycytes are endowed with neural stem cell properties and may respond to dietary or reproductive cues by modulating hypothalamic neurogenesis. Tanycytes could thus constitute the missing link in the loop connecting behavior, hormonal changes, signal transduction, central neuronal activation and, finally, behavior again. In this article, we will examine these recent advances in the understanding of tanycytic plasticity and function in the hypothalamus and the underlying molecular mechanisms. We will also discuss the putative involvement and therapeutic potential of hypothalamic tanycytes in metabolic and fertility disorders

Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons

International audienceHypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the hypothalamic arcuate nucleus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive Connexin-43 gap-junction-mediated metabolic networks by arcuate tanycytes. Selectively suppressing either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism

MCH Regulates SIRT1/FoxO1 and Reduces POMC Neuronal Activity to Induce Hyperphagia, Adiposity, and Glucose Intolerance

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Elevated prenatal anti-Müllerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood

International audiencePolycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin-releasing hormone (GnRH) release, and anti-Müllerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS-like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood