TY - JOUR

T1 - Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions

AU - Imbernon, Monica

AU - Saponaro, Chiara

AU - Helms, Hans Christian Cederberg

AU - Duquenne, Manon

AU - Fernandois, Daniela

AU - Deligia, Eleonora

AU - Denis, Raphael G.P.

AU - Chao, Daniela Herrera Moro

AU - Rasika, Sowmyalakshmi

AU - Staels, Bart

AU - Pattou, François

AU - Pfrieger, Frank W.

AU - Brodin, Birger

AU - Luquet, Serge

AU - Bonner, Caroline

AU - Prevot, Vincent

N1 - Funding Information: This work was supported by the European Research Council (ERC) Synergy grant no. 810331 to V.P., H2020 - MSCA grant no. 748134 to M.I., the Agence National de la Recherche (ANR, France) grant ANR-15-CE14-0025 to V.P., European Genomic Institute for Diabetes (EGID, ANR-10-LABX-0046 and I-SITE ULNE ANR-16-IDEX-0004 to V.P., F.P., and B.S.), the Conseil Regional Nord-Pas de Calais (to C.B.), and funding from Novo Nordisk A/S (S.L. and V.P.). H.C.C.H. was supported by a fellowship from Novo Nordisk A/S. B.S. is a recipient of an ERC Advanced Grant ( 694717 ). We thank Marc R. Montminy (Salk Institute, La Jolla, CA, USA) for his generous gift of the phopho-CREB antibody. We thank Emilie Caron (metabolic cages), Nathalie Jouy and Amandine Legrand (cell sorting), Antonino Bongiovani (imaging facility) from the BioImaging Center of Lille (BiCeL), and Julien Devassine (animal core facility) of the PLBS UAR2014-US41 for their expert technical support. Funding Information: This work was supported by the European Research Council (ERC) Synergy grant no. 810331 to V.P. H2020-MSCA grant no. 748134 to M.I. the Agence National de la Recherche (ANR, France) grant ANR-15-CE14-0025 to V.P. European Genomic Institute for Diabetes (EGID, ANR-10-LABX-0046 and I-SITE ULNE ANR-16-IDEX-0004 to V.P. F.P. and B.S.), the Conseil Regional Nord-Pas de Calais (to C.B.), and funding from Novo Nordisk A/S (S.L. and V.P.). H.C.C.H. was supported by a fellowship from Novo Nordisk A/S. B.S. is a recipient of an ERC Advanced Grant (694717). We thank Marc R. Montminy (Salk Institute, La Jolla, CA, USA) for his generous gift of the phopho-CREB antibody. We thank Emilie Caron (metabolic cages), Nathalie Jouy and Amandine Legrand (cell sorting), Antonino Bongiovani (imaging facility) from the BioImaging Center of Lille (BiCeL), and Julien Devassine (animal core facility) of the PLBS UAR2014-US41 for their expert technical support. M.I. and V.P. conceived the study. M.I. C.S. H.C.C.H. M.D. D.F. and E.D. carried out the experiments. H.C.C.H. and B.B. set up the classical BBB model and performed in vitro barrier experiments. M.I. R.G.P.D. D.H.M.C. and S.L. conducted metabolic phenotyping. D.F. and M.I. performed microdialysis experiments. F.W.P. generated the iBot animal model. M.I. C.S. B.S. F.P. S.L. C.B. and V.P. designed and planned the experiments. M.I. C.S. C.B. and V.P. wrote the paper. S.R. edited the manuscript. All authors contributed to the preparation of the manuscript. The authors declare no competing interests. Publisher Copyright: © 2022 Elsevier Inc.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - AAV

KW - arcuate nucleus of the hypothalamus

KW - botulinum toxin

KW - brain

KW - fatty acid oxidation

KW - GLP1 analog

KW - GLP1R agonist

KW - median eminence

KW - tanycyte

KW - weight loss

U2 - 10.1016/j.cmet.2022.06.002

DO - 10.1016/j.cmet.2022.06.002

M3 - Journal article

C2 - 35716660

AN - SCOPUS:85132994780

VL - 34

SP - 1054-1063.e7

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 7

ER -