Nature (London), 2024-05, Vol.629 (8014), p.1133-4
- Petersen, Jonas
- Ludwig, Mette Q
- Juozaityte, Vaida
- Ranea-Robles, Pablo
- Svendsen, Charlotte
- Hwang, Eunsang
- Kristensen, Amalie W
- Fadahunsi, Nicole
- Lund, Jens
- Breum, Alberte W
- Mathiesen, Cecilie V
- Sachs, Luisa
- Moreno-Justicia, Roger
- Rohlfs, Rebecca
- d, James C
- Douros, Jonathan D
- Finan, Brian
- Portillo, Bryan
- Grose, Kyle
- Petersen, Jacob E
- Trauelsen, Mette
- Feuchtinger, Annette
- DiMarchi, Richard D
- Schwartz, Thue W
- Deshmukh, Atul S
- Thomsen, Morten B
- Kohlmeier, Kristi A
- Williams, Kevin W
- Pers, Tune H
- Frølund, Bente
- Strømgaard, Kristian
- Klein, Anders B
- Clemmensen, Christoffer
2024
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- Autor(en) / Beteiligte
- Petersen, Jonas
- Ludwig, Mette Q
- Juozaityte, Vaida
- Ranea-Robles, Pablo
- Svendsen, Charlotte
- Hwang, Eunsang
- Kristensen, Amalie W
- Fadahunsi, Nicole
- Lund, Jens
- Breum, Alberte W
- Mathiesen, Cecilie V
- Sachs, Luisa
- Moreno-Justicia, Roger
- Rohlfs, Rebecca
- d, James C
- Douros, Jonathan D
- Finan, Brian
- Portillo, Bryan
- Grose, Kyle
- Petersen, Jacob E
- Trauelsen, Mette
- Feuchtinger, Annette
- DiMarchi, Richard D
- Schwartz, Thue W
- Deshmukh, Atul S
- Thomsen, Morten B
- Kohlmeier, Kristi A
- Williams, Kevin W
- Pers, Tune H
- Frølund, Bente
- Strømgaard, Kristian
- Klein, Anders B
- Clemmensen, Christoffer
- Titel
- GLP-1-directed NMDA receptor antagonism for obesity treatment
- Ist Teil von
- Nature (London), 2024-05, Vol.629 (8014), p.1133-4
- Ort / Verlag
- London: Nature Publishing Group
- Erscheinungsjahr
- 2024
- Beschreibungen/Notizen
- 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-l-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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836eISSN: 1476-4687DOI: 10.1O38/s41586-O24-O7419-8Titel-ID: cdi_proquest_journals_3063798794
- Format
- –
- Schlagworte
- Alzheimer's disease, Animal models, Body fat, Body weight, Brain, Brain stem, Calories, Dizocilpine, Dyslipidemia, Energy, Food, Genome-wide association studies, Glucagon, Glucagon-like peptide 1, Glucose, Glutamate receptors, Glutamatergic transmission, Glutamic acid receptors (ionotropic), Hyperglycemia, Hyperthermia, Hypothalamus, Insulin, Ion channels, Metabolic disorders, Metabolism, N-Methyl-D-aspartic acid receptors, Neural plasticity, Neurotransmission, Obesity, Peptides, Physiological effects, Plasma, Receptors, Synaptic plasticity, Weight control