GLP-1-directed NMDA receptor antagonism for obesity treatment

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

GLP-1-directed NMDA receptor antagonism for obesity treatment. / 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.; Frølund, Bente; Strømgaard, Kristian; Klein, Anders B.; Clemmensen, Christoffer.

In: Nature, Vol. 629, No. 8014, 2024, p. 1133–1141.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Petersen, J, Ludwig, MQ, Juozaityte, V, Ranea-Robles, P, Svendsen, C, Hwang, E, Kristensen, AW, Fadahunsi, N, Lund, J, Breum, AW, Mathiesen, CV, Sachs, L, Moreno-Justicia, R, Rohlfs, R, Ford, JC, Douros, JD, Finan, B, Portillo, B, Grose, K, Petersen, JE, Trauelsen, M, Feuchtinger, A, DiMarchi, RD, Schwartz, TW, Deshmukh, AS, Thomsen, MB, Kohlmeier, KA, Williams, KW, Pers, TH, Frølund, B, Strømgaard, K, Klein, AB & Clemmensen, C 2024, 'GLP-1-directed NMDA receptor antagonism for obesity treatment', Nature, vol. 629, no. 8014, pp. 1133–1141. https://doi.org/10.1038/s41586-024-07419-8

APA

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., ... Clemmensen, C. (2024). GLP-1-directed NMDA receptor antagonism for obesity treatment. Nature, 629(8014), 1133–1141. https://doi.org/10.1038/s41586-024-07419-8

Vancouver

Petersen J, Ludwig MQ, Juozaityte V, Ranea-Robles P, Svendsen C, Hwang E et al. GLP-1-directed NMDA receptor antagonism for obesity treatment. Nature. 2024;629(8014):1133–1141. https://doi.org/10.1038/s41586-024-07419-8

Author

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. ; Frølund, Bente ; Strømgaard, Kristian ; Klein, Anders B. ; Clemmensen, Christoffer. / GLP-1-directed NMDA receptor antagonism for obesity treatment. In: Nature. 2024 ; Vol. 629, No. 8014. pp. 1133–1141.

Bibtex

@article{40efbbdab63d4d00a73145075e427939,
title = "GLP-1-directed NMDA receptor antagonism for obesity treatment",
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.",
author = "Jonas Petersen and Ludwig, {Mette Q.} and Vaida Juozaityte and Pablo Ranea-Robles and Charlotte Svendsen and Eunsang Hwang and Kristensen, {Amalie W.} and Nicole Fadahunsi and Jens Lund and Breum, {Alberte W.} and Mathiesen, {Cecilie V.} and Luisa Sachs and Roger Moreno-Justicia and Rebecca Rohlfs and Ford, {James C.} and Douros, {Jonathan D.} and Brian Finan and Bryan Portillo and Kyle Grose and Petersen, {Jacob E.} and Mette Trauelsen and Annette Feuchtinger and DiMarchi, {Richard D.} and Schwartz, {Thue W.} and Deshmukh, {Atul S.} and Thomsen, {Morten B.} and Kohlmeier, {Kristi A.} and Williams, {Kevin W.} and Pers, {Tune H.} and Bente Fr{\o}lund and Kristian Str{\o}mgaard and Klein, {Anders B.} and Christoffer Clemmensen",
note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",
year = "2024",
doi = "10.1038/s41586-024-07419-8",
language = "English",
volume = "629",
pages = "1133–1141",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "nature publishing group",
number = "8014",

}

RIS

TY - JOUR

T1 - GLP-1-directed NMDA receptor antagonism for obesity treatment

AU - Petersen, Jonas

AU - Ludwig, Mette Q.

AU - Juozaityte, Vaida

AU - Ranea-Robles, Pablo

AU - Svendsen, Charlotte

AU - Hwang, Eunsang

AU - Kristensen, Amalie W.

AU - Fadahunsi, Nicole

AU - Lund, Jens

AU - Breum, Alberte W.

AU - Mathiesen, Cecilie V.

AU - Sachs, Luisa

AU - Moreno-Justicia, Roger

AU - Rohlfs, Rebecca

AU - Ford, James C.

AU - Douros, Jonathan D.

AU - Finan, Brian

AU - Portillo, Bryan

AU - Grose, Kyle

AU - Petersen, Jacob E.

AU - Trauelsen, Mette

AU - Feuchtinger, Annette

AU - DiMarchi, Richard D.

AU - Schwartz, Thue W.

AU - Deshmukh, Atul S.

AU - Thomsen, Morten B.

AU - Kohlmeier, Kristi A.

AU - Williams, Kevin W.

AU - Pers, Tune H.

AU - Frølund, Bente

AU - Strømgaard, Kristian

AU - Klein, Anders B.

AU - Clemmensen, Christoffer

N1 - Publisher Copyright: © The Author(s) 2024.

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-024-07419-8

DO - 10.1038/s41586-024-07419-8

M3 - Journal article

C2 - 38750368

AN - SCOPUS:85192940391

VL - 629

SP - 1133

EP - 1141

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 8014

ER -

ID: 393264756