Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions

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Imbernon, Monica | Saponaro, Chiara | Helms, Hans Christian Cederberg | Duquenne, Manon | Fernandois, Daniela | Deligia, Eleonora | Denis, Raphael G.P. | Chao, Daniela Herrera Moro | Rasika, Sowmyalakshmi | Staels, Bart | Pattou, François | Pfrieger, Frank | Brodin, Birger | Luquet, Serge | Bonner, Caroline | Prevot, Vincent

Edité par CCSD ; Elsevier -

International audience. Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recentlybeen approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolicbenefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutideis shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes,bypassing the blood-brain barrier. Selectively silencing GLP1R in tanycytes or inhibiting tanycytic transcytosisby botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activationof target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fatmass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activationof hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport intothe mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis.

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