open access publication

Article, 2024

GLP-1-directed NMDA receptor antagonism for obesity treatment

Nature, ISSN 0028-0836, 1476-4687, Volume 629, 8014, Pages 1133-1141, 10.1038/s41586-024-07419-8

Contributors

Petersen, Jonas O 0000-0002-6219-0271 [1] Ludwig, Mette Q 0000-0002-7814-3859 [1] Juozaityte, Vaida 0000-0003-3403-6143 [1] Ranea-Robles, Pablo 0000-0001-6478-3815 [1] Svendsen, Charlotte Sashi Aier 0000-0002-8329-319X [1] Hwang, Eun-Sang [2] Kristensen, Amalie W. [1] Fadahunsi, Nicole [1] Lund, Jens Teglgaard 0000-0003-2338-6033 [1] Breum, Alberte Wollesen 0000-0002-8399-4308 [1] Mathiesen, Cecilie Vad 0000-0002-8325-5898 [1] Sachs, Luisa [1] Moreno-Justicia, Roger 0000-0002-8587-4772 [1] Rohlfs, Rebecca [3] Ford, James C. [3] Douros, Jonathan D 0000-0003-2299-6163 [3] Finan, Brian [3] Portillo, Bryan [2] Grose, Kyle C [2] Petersen, Jacob Emil 0000-0002-2116-1626 [1] Trauelsen, Mette Hyldgaard 0000-0002-6908-106X [1] Feuchtinger, Annette [4] Dimarchi, Richard D [5] Schwartz, Thue Walther 0000-0002-0261-6904 [1] Deshmukh, Atul Shahaji 0000-0002-2278-1843 [1] Thomsen, Morten Bækgaard 0000-0002-2469-6458 [1] Kohlmeier, Kristi Anne 0000-0003-0183-3816 [1] Williams, Kevin W. [2] Pers, Tune Hannes 0000-0003-0207-4831 [1] Frølund, Bente Flensborg 0000-0001-5476-6288 [1] Strømgaard, Kristian 0000-0003-2206-4737 [1] Klein, Anders Bue 0000-0002-0236-3089 [1] Clemmensen, Christoffer 0000-0003-2456-9667 (Corresponding author) [1]

Affiliations

  1. [1] University of Copenhagen
    2. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  2. [2] The University of Texas Southwestern Medical Center
    3. [NORA names: United States; America, North; OECD];
  3. [3] Novo Nordisk (United States)
    4. [NORA names: United States; America, North; OECD];
  4. [4] Core Facility Pathology & Tissue Analytics, Helmholtz Munich, Neuherberg, Germany
    5. [NORA names: Germany; Europe, EU; OECD];
  5. [5] Indiana University Bloomington
    6. [NORA names: United States; America, North; OECD]

Abstract

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.

Keywords

GLP-1 receptor agonism, MK-801, N-methyl-D-aspartate, N-methyl-D-aspartate receptor antagonism, N-methyl-D-aspartate receptor antagonist MK-801, N-methyl-d-aspartate receptor-mediated synaptic plasticity, NMDA receptor antagonism, agonism, antagonism, antagonist MK-801, association studies, body, brain, brain regions, brainstem, cation channels, channel, delivery, development, disease, dyslipidaemia, effective obesity treatment, engineering, feasibility, genome-wide association studies, glucagon-like peptide-1, glutamatergic neurotransmission, homeostasis1, hyperglycaemia, hypothalamus, metabolic diseases, models of metabolic disease, modulation, molecules, monotherapy, neuroplasticity, neurotransmission, obesity, obesity treatment, peptide-1, peptide-mediated targeting, plasticity, preclinical development, process, receptor agonism, receptor antagonism, receptor modulators, region, reverse obesity, rodent models, rodent models of metabolic disease, study, synaptic plasticity, target, therapeutic potential, treatment

Funders

  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Lundbeck Foundation
  • Novo Nordisk Foundation
  • National Research Foundation of Korea

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