Understanding how tanycytes, which act as gatekeepers between the brain and body, influence metabolism and cognitive aging throughout the lifespan
As a Synergy project funded by the European Research Council (ERC), the WATCH project (Well-Aging and the Tanycytic Control of Health) brings together the teams of three Principal Investigators (PIs): Vincent Prevot, a neuroendocrinologist working for the French national health research institute (Inserm), in Lille, France; Markus Schwaninger, a neurologist at the University of Lübeck, Germany; and Ruben Nogueiras, an expert in molecular metabolism at the University of Santiago de Compostela in Spain. The joint efforts of these teams are aimed at elucidating how a small and highly specialized population of brain cells called tanycytes, which lie at the interface between the brain and body, are involved in controlling a variety of physiological processes, and the implications of their function or dysfunction for healthy aging.
The survival of an organism depends on the ability of the brain to detect changes in the internal and external environment of the body, and to direct the appropriate physiological responses in order to maintain equilibrium. This accurate and timely exchange of information between the brain and other organs requires the passage of various blood-borne signals such as hormones or metabolites from one compartment to the other, and the breakdown of this communication with age or disease is associated, among others, with metabolic imbalances and neurodegenerative disorders. Despite its small size, the hypothalamus contains a disproportionately large number of regions and neuronal populations that control a wide array of physiological processes by either producing or responding to such signals. Tanycytes, peculiar glial cells that occupy a unique position in the brain, being in contact both with the blood circulation at one end and with the cerebrospinal fluid in the third ventricle, a part of the brain’s interconnected canal system, at the other, are ideally placed to detect and control the passage of such signals depending on physiological needs.
The WATCH consortium, since its creation three years ago, has greatly contributed to our knowledge of these enigmatic cells and their diverse roles. It has long been known that tanycytes, by undergoing structural remodeling, control the secretion of the reproductive hormone, gonadotropin-releasing hormone, into the blood, and are also involved in regulating the secretion of thyroid hormones. WATCH members have provided definitive proof, notably, that tanycytes also express receptors for and are responsible for transporting various metabolic signals such as leptin, a hormone secreted by fat cells in the periphery that signals satiety, or FGF21, a peptide secreted by the liver, into the hypothalamus to their target neurons. The failure of this transport leads to obesity, type 2 diabetes, or alterations in how the body burns fuels such as lipids to generate heat, while reestablishing the access of these signals to hypothalamic circuits that respond to them restores or improves energy balance. Similarly, the WATCH project has shown that anti-obesity drugs such as liraglutide use the same mechanism to enter the hypothalamus and exert their effects. In the other direction, tanycytes also shuttle substances that need to be cleared from the brain into the blood circulation. This is the case with Tau, a protein whose unnatural accumulation in the brain is associated with Alzheimer’s disease and other neurodegenerative disorders. Intriguingly, it is not just tanycytic transport but tanycytes themselves that break down in Alzheimer’s disease, pointing to a role for tanycytes in the pathogenesis of this and possibly other forms of age-related cognitive decline.
These findings of the WATCH project, made possible by the close interactions and complementarity of skills and interest of the three teams, highlight the role of tanycytes as linchpins in the communication between the brain and periphery, and support the view that the protection or restoration of tanycytic structure, plasticity and function could represent valuable and druggable therapeutic targets for a range of disorders.
