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Petersen, J.* ; Ludwig, M.Q.* ; Juozaityte, V.* ; Ranea-Robles, P.* ; Svendsen, C.* ; Hwang, E.* ; Kristensen, A.W.* ; Fadahunsi, N.* ; Lund, J.* ; Breum, A.W.* ; Mathiesen, C.V.* ; Sachs, L.* ; Moreno-Justicia, R.* ; Rohlfs, R.* ; Ford, J.C.* ; Douros, J.D.* ; Finan, B.* ; Portillo, B.* ; Grose, K.* ; Petersen, J.E.* ; Trauelsen, M.* ; Feuchtinger, A. ; DiMarchi, R.D.* ; Schwartz, T.W.* ; Deshmukh, A.S.* ; Thomsen, M.B.* ; Kohlmeier, K.A.* ; Williams, K.W.* ; Pers, T.H.* ; Frølund, B.* ; Strømgaard, K.* ; Klein, A.B.* ; Clemmensen, C.*

GLP-1-directed NMDA receptor antagonism for obesity treatment.

Nature 629, 1133-1141 (2024)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Body-temperature; Food-intake; Mk-801; Memantine; Weight; Activation; Tolerance; Reverses; Neurons
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Quellenangaben Band: 629, Heft: 8014, Seiten: 1133-1141 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) CF Pathology & Tissue Analytics (CF-PTA)
POF Topic(s) 30202 - Environmental Health
PSP-Element(e) A-630600-001
Förderungen Novo Nordisk Foundation Center for Basic Metabolic Research
BioInnovation Institute
Novo Nordisk Foundation
National Research Foundation of Korea, NRF
Novo Nordisk Foundation (NNF)
Novo Nordisk Foundation Center for Protein Research
Lundbeck Foundation
DOI 10.1038/s41586-024-07419-8
WOS ID 001443169900020
WOS ID 001262383500012
Scopus ID 85192940391
PubMed ID 38750368
Erfassungsdatum 2024-06-12
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