What if Aging Well Depended on the Gateway of Hormones into the Brain?

Researcher Vincent Prévot has recently obtained a 9.8-million-euro European Research Council (ERC) Synergy Grant to conduct the WATCH project (Well-Aging and the Tanycytic Control of Health). He is giving himself six years to ascertain whether a deficiency in the transit to the brain of hormones circulating in the blood is implicated in cognitive decline. This funding represents a crowning achievement in what has been a rich career in neuroendocrinology so far.

Vincent Prévot

Vincent Prévot has extensive expertise, excelling not just in the neurosciences, but also in endocrinology. From his doctoral thesis, his has been a flawless career in neuroendocrinology, a field in which the neurosciences and endocrinology meet. A field which concerns the many complex interactions occurring between the peripheral metabolism and cerebral function. In one direction, the brain controls the release of hormones which act on the organs and peripheral functions and, in the other, certain compounds in the blood sound the alarm to inform the brain of the physiological state of the body. The aim is to be able to identify the players, how they function, and why.

For Vincent Prévot, it is a vocation which he can more or less trace back to his childhood:  "Passionate about reptiles, I used to collect them, and I did numerous internships at the Chizé Center for Biological Studies (CNRS) which studies them in their natural environment. One difficulty was getting them to reproduce in captivity despite managing this several times at home. I found it fascinating how the brain controls these functions – how it controls whether or not reproduction takes place".

An adaptable barrier

Keen to find out more, Vincent Prévot completed a master’s at Orsay, and then headed to Lille to prepare a doctorate at Jean-Claude Beauvillain’s Laboratory of Neuroendocrinology and Neuronal Pathophysiology (Inserm Unit 422) – a cutting-edge laboratory in the relationship between the brain and reproduction. There he worked on the hypothalamus, a brain region involved in this function. He was particularly interested in the median eminence, a structure located at the base of the hypothalamus. "The median eminence is equipped with very specific cells, called tanycytes. Their cell body, which contains the nucleus, bathes in the cerebrospinal fluid and very long extensions project to the outer surface of the brain. These cells physically interact with neurons that secrete neurohormones which control the activity of the pituitary gland. A gland involved in regulating essential functions, such as growth, reproduction, and stress." But above all, as Vincent Prévot will demonstrate, it is via these tanycytes that certain metabolic hormones transit to the brain. These cells are attached to each other by tight junctions which form an adaptable barrier. Everywhere else in the brain, this passage is blocked by the blood-brain barrier. It is the only area which is not sealed off. 

During his doctoral thesis, Vincent Prévot demonstrated in rodents that these tanycytes present morphological plasticity which controls the release of the reproductive neurohormone GnRH during the ovarian cycle. He then headed to the Oregon Health Science University in the USA, to join the laboratory of Sergio R. Ojeda, expert in the communication between the glial cells (of which the tanycytes form part) and the GnRH neurons. During this three-year postdoctoral sojourn, he described the communication pathways of the tanycytes and their functioning.

When he returned to France in 2002, he joined Inserm as an associate researcher and set up a group in the unit in which he had prepared his doctoral thesis, in Lille. Four years later, he took the helm of a laboratory (Unit 816) and headed up a team at the Jean-Pierre Aubert Research Center (Unit 1172 Inserm/Université de Lille/University Hospital Lille, Development and Plasticity of the Neuroendocrine Brain), determined to deepen his knowledge of the median eminence.

From the regulation of reproductive functions to that of appetite

Figure showing the tight junction proteins (green fluorescence) around the cellular bodies of tanycytes (white fluorescence) bordering the third ventricle, as well as capillaries of the blood-brain barrier and proteins of "fenestered" i.e. permeable capillaries (red fluorescence).
Figure showing the labeling of the tight junction proteins (green fluorescence) around the tanycyte cell bodies (white fluorescence) lining the third ventricle, as well as capillaries of the blood-brain barrier and proteins of "fenestrated" (i.e. permeable) capillaries (red fluorescence). Credits: Inserm/V. Prévot/B. Dehouck/F. Langlet

Vincent Prévot then intensified his research into the relationship between the brain and peripheral hormones. He worked on the establishment of the neuronal-glial circuit controlling reproductive functions during embryonic and postnatal development and began to take a close look at the regulation of appetite. In 2013, he demonstrated with his team - notably with Bénédicte Dehouck - that hypoglycemia promotes vessel opening under the command of the tanycytes, in order to inform the brain of this state. The following year, he proved that leptin, the hormone of satiety, is transported from the blood to the brain by the tanycytes, really highlighting their role as the brain’s "gatekeepers". In obese subjects, however, this transport function is altered, partially explaining the loss of appetite control.

Furthermore, a study conducted in collaboration with Sébastien Bouret, who directs the US branch of the Neurobese International Associated Laboratory, in Los Angeles, shows that childhood obesity alters the transport functions performed by the tanycytes for another metabolic hormone, ghrelin. Like leptin, it is implicated in the postnatal programming of the brain. From the alteration of its transport results an early alteration of the establishment of neuronal circuits involved in the control of food intake, thereby predisposing to metabolic diseases. "It was proof that the metabolism can format neuronal circuits and have long-term consequences, and that the tanycytes could play a role in this process", clarifies Prévot.

This latest research represents a turning point for the researcher. With obesity being a risk factor for dementia and leptin being able to modulate brain development, what if the transit of peripheral hormones – or, on the contrary, their blockade at tanycytic level – was to contribute to proper brain functioning or, conversely, to cognitive decline in adulthood?

The WATCH project

To find out more, he set up a project known as WATCH: Well-Aging and the Tanycytic Control of Health. Preliminary research points to a positive response, but this will need to be confirmed in rodents and, most importantly, in humans. For this, the researcher has joined forces with two other teams, one led by Markus Schwaninger, director of the Institute of Pharmacology and Clinical Toxicology at Lübeck University in Germany, and the other led by Rubén Nogueiras, peripheral metabolism specialist at St Jacques de Compostelle University in Spain. The expertise of this trio and the importance of the issues surrounding aging in good health are such that Vincent Prévot has been awarded an ERC Synergy grant of 9.8 million euro (4.5 million for his team, 2.8 for Markus Schwaninger's group and et 2.3 millions for Rubén Nogueiras's).

To carry out their project, the researchers will begin by using a multitude of genetically-modified mouse models to study the effect of the altered transport of peripheral hormones to the brain by the tanycytes. They will then analyze the coordination of this transport with the secretion of the neurohormones of the hypothalamus and the impacts on the aging of the animals.

Then, they will work with obese patients who will volunteer to undergo various biochemical, cognitive and brain imaging analyses. The researchers will measure the ratio between level of leptin in the blood and in the cerebrospinal fluid, and the composition of the latter. The volunteers will then be administered, for three months, a compound meant to improve tanycytic transport. "We will see whether the cerebral/peripheral leptin ratio has been modified, whether the hypothalamic activity has changed, and whether the scores on the cognitive, depression and motivation tests have changed", explains the researcher. "If our hypothesis is correct, this will mean that the access of the peripheral hormones to the brain is a factor of good health for the latter whereas the loss of this access leads to a deterioration in its functions". This will of course open up new therapeutic avenues in the fight against cognitive decline and for the possibility to age in good health.