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GLP-1-directed NMDA receptor antagonism for obesity treatment

Author

Listed:
  • Jonas Petersen

    (University of Copenhagen
    University of Copenhagen)

  • Mette Q. Ludwig

    (University of Copenhagen)

  • Vaida Juozaityte

    (University of Copenhagen)

  • Pablo Ranea-Robles

    (University of Copenhagen)

  • Charlotte Svendsen

    (University of Copenhagen)

  • Eunsang Hwang

    (the University of Texas Southwestern Medical Center at Dallas)

  • Amalie W. Kristensen

    (University of Copenhagen)

  • Nicole Fadahunsi

    (University of Copenhagen)

  • Jens Lund

    (University of Copenhagen)

  • Alberte W. Breum

    (University of Copenhagen)

  • Cecilie V. Mathiesen

    (University of Copenhagen)

  • Luisa Sachs

    (University of Copenhagen)

  • Roger Moreno-Justicia

    (University of Copenhagen)

  • Rebecca Rohlfs

    (Novo Nordisk Research Center Indianapolis)

  • James C. Ford

    (Novo Nordisk Research Center Indianapolis)

  • Jonathan D. Douros

    (Novo Nordisk Research Center Indianapolis)

  • Brian Finan

    (Novo Nordisk Research Center Indianapolis)

  • Bryan Portillo

    (the University of Texas Southwestern Medical Center at Dallas)

  • Kyle Grose

    (the University of Texas Southwestern Medical Center at Dallas)

  • Jacob E. Petersen

    (University of Copenhagen)

  • Mette Trauelsen

    (University of Copenhagen)

  • Annette Feuchtinger

    (Helmholtz Munich)

  • Richard D. DiMarchi

    (Indiana University)

  • Thue W. Schwartz

    (University of Copenhagen)

  • Atul S. Deshmukh

    (University of Copenhagen)

  • Morten B. Thomsen

    (University of Copenhagen)

  • Kristi A. Kohlmeier

    (University of Copenhagen)

  • Kevin W. Williams

    (the University of Texas Southwestern Medical Center at Dallas)

  • Tune H. Pers

    (University of Copenhagen)

  • Bente Frølund

    (University of Copenhagen)

  • Kristian Strømgaard

    (University of Copenhagen)

  • Anders B. Klein

    (University of Copenhagen)

  • Christoffer Clemmensen

    (University of Copenhagen)

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.

Suggested Citation

  • Jonas Petersen & Mette Q. Ludwig & Vaida Juozaityte & Pablo Ranea-Robles & Charlotte Svendsen & Eunsang Hwang & Amalie W. Kristensen & Nicole Fadahunsi & Jens Lund & Alberte W. Breum & Cecilie V. Math, 2024. "GLP-1-directed NMDA receptor antagonism for obesity treatment," Nature, Nature, vol. 629(8014), pages 1133-1141, May.
    • Handle: RePEc:nat:nature:v:629:y:2024:i:8014:d:10.1038_s41586-024-07419-8
    DOI: 10.1038/s41586-024-07419-8
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