The tanycytic Hippo pathway as a new druggable target for energy metabolism control – HippoTan

Tanycytes are hypothalamic ependymoglial cells controlling the remodelling of energy homeostasis circuits thanks to their neural stem cell properties. Deregulated cell proliferation and hypothalamic neurogenesis have been associated with obesity and diabetes. However, the molecular control of tanycyte neural stem cell properties and hypothalamic neurogenesis have remained largely unknown. We recently identified a signalling pathway, the Hippo pathway (HP), which regulates both the proliferation of adult tanycytes and energy homeostasis, and showed that activation of the HP output in tanycytes exerts adverse metabolic effects. This project aims at developing a new strategy to inhibit the HP output in tanycytes, in order to restore energy homeostasis. The specific objectives are: 1) to explore the mechanisms by which the HP in tanycytes controls cell proliferation and energy homeostasis; 2) to develop new inhibitors of the HP output to efficiently block tanycyte proliferation; 3) to develop an innovative strategy to selectively deliver our new inhibitors to tanycytes in vivo and evaluate their impact on energy homeostasis control. This interdisciplinary project will involve the expertise of biologists and chemists and combine molecular modelling, organic chemistry, neuroanatomy, cellular and molecular biology, and physiology.