Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions.
AAV
GLP1 analog
GLP1R agonist
arcuate nucleus of the hypothalamus
botulinum toxin
brain
fatty acid oxidation
median eminence
tanycyte
weight loss
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
05 07 2022
05 07 2022
Historique:
received:
31
08
2020
revised:
08
08
2021
accepted:
01
06
2022
pubmed:
19
6
2022
medline:
9
7
2022
entrez:
18
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35716660
pii: S1550-4131(22)00222-4
doi: 10.1016/j.cmet.2022.06.002
pmc: PMC7613793
mid: EMS156428
pii:
doi:
Substances chimiques
Liraglutide
839I73S42A
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1054-1063.e7Subventions
Organisme : European Research Council
ID : 810331
Pays : International
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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