GLP-1-directed NMDA receptor antagonism for obesity treatment

• 成果类型: Article
• 署名作者: 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; Ford, 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.; Frlound, Bente; Stromgaard, Kristian; Klein, Anders B.; Clemmensen, Christoffer
• 署名单位: Novo Nordisk Foundation; University of Copenhagen; University of Copenhagen; University of Texas System; University of Texas Southwestern Medical Center; Indiana University System; Indiana University Bloomington; University of Copenhagen
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3827
• DOI: 10.1038/s41586-024-07419-8
• 发表日期: 2024-05-30
• 页码: 1133-+
• 关键词: body-temperature; food-intake; mk-801; memantine; weight; activation; tolerance; reverses; neurons

摘要

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 homeostasis(1). 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.