Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions

Monica Imbernon (1, 2, 3, 4) , Chiara Saponaro , Hans Christian Cederberg Helms (5) , Manon Duquenne (1) , Daniela Fernandois (1, 2, 3, 4) , Eleonora Deligia (1, 2, 3, 4) , Raphael G.P. Denis (6) , Daniela Herrera Moro Chao , Sowmyalakshmi Rasika (7) , Bart Staels (8, 2, 4) , François Pattou (9) , Frank Pfrieger (10) , Birger Brodin (5) , Serge Luquet (11) , Caroline Bonner (9) , Vincent Prevot (12)

1 LilNCog - Lille Neurosciences & Cognition - U 1172
2 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
3 FHU 1 000 jours pour la santé
4 EGID - Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508
5 UCPH - University of Copenhagen = Københavns Universitet
6 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
7 PROTECT - Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies
8 RNMCD - Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011
9 RTD - Recherche translationnelle sur le diabète - U 1190
10 INCI - Institut des Neurosciences Cellulaires et Intégratives
11 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
12 Equipe "Development and Plasticity of the Neuroendocrine Brain" - LilNCog

Liraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recently been approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolic benefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutide is 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 transcytosis by botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activation of target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fat mass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activation of hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport into the mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis.

Domaines: Endocrinologie et métabolisme; Alimentation et Nutrition; Pharmacologie

Monica Imbernon, Chiara Saponaro, Hans Christian Cederberg Helms, Manon Duquenne, Daniela Fernandois, et al.. Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions. Cell Metabolism, 2022, 34 (7), pp.1054 - 1063.e7. ⟨10.1016/j.cmet.2022.06.002⟩. ⟨hal-03778811⟩