The brain controls the release of hormones that act on peripheral organs. And conversely, certain molecules released by peripheral organs are carried by the blood and inform the brain about the physiological state of the organism. The key is to identify these molecular players and find out their mode of action. Within the brain, a small structure known as hypothalamus, is the main centre for sensing and responding to signals coming from different peripheral organs. At the base of the hypothalamus is present one of the circumventricular organs (CVO) known as median eminence (ME). A unique feature of ME is the absence of blood-brain barrier (BBB) and the presence of specialized glial cells known as tanycytes. The cell bodies of tanycytes are bathed in cerebrospinal fluid (transparent liquid in whih the brain and spinal cord are immersed) and their long projections extend to the external surface of the brain. Tanycytes interact with neurons that secrete neurohormones that drive the activity of the pituitary gland. These interactions play extremely important role in a regulating a number of essential body functions such as growth, reproduction, stress, etc. Tanycytes are highly versatile cells and act as gate keepers by controlling the exchange of metabolic signals between the peripheral blood and the CSF. In a previously published study, Vincent Prévot has shown that leptin, the satiety hormone, is transported from the blood to the brain by tanycytes, demonstrating their role as “gate keepers” of the brain. However, this transport function is impaired in obese individuals, partly explaining the loss of control on the appetite. In another study, it has been found that childhood obesity affects the tanycyte mediated transport of another metabolic hormone known as ghrelin. Similar to leptin, ghrelin is also involved in the establishment of neural circuits involved in the control of food intake, thus predisposing an individual to metabolic diseases. Some studies have demonstrated that obesity, a metabolic disorder, is a risk factor for dementia.

To carry out the WATCH project, the researchers will use a multitude of genetically modified mouse models to study the effect of the alteration of the transport of peripheral hormones in the brain by tanycytes. They will analyze the correlation of this transport with the secretion of neurohormones from the hypothalamus and the consequences on the aging of animals. Secondly, they will work with obese patients. Volunteers will undergo various biochemical, cognitive and brain imaging tests. The researchers will notably measure the relationship between the level of leptin in the blood and in the cerebrospinal fluid, and the composition of the latter. The volunteers will then receive, for three months, a drug supposed to improve tanycytic transport. At the end of the study, the ratio of cerebral leptin / peripheral leptin will be calculated to observe whether there has been any change after the drug administration, the changes in the hypothalamic activity, if any, will be measured, and the changes in cognitive tests, depression and motivation will be calculated.