Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment

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

Standard

Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment. / Fadahunsi, Nicole; Petersen, Jonas Odgaard; Metz, Sophia; Jakobsen, Alexander; Mathiesen, Cecilie Vad; Buch-Rasmussen, Alberte Silke; Kurgan, Nigel Kilty; Larsen, Jeppe Kjærgaard; Andersen, Rita Chan; Topilko, Thomas; Svendsen, Charlotte; Apuschkin, Mia; Skovbjerg, Grethe; Schmidt, Jan Hendrik; Houser, Grace Anne; Jager, Sara Elgaard; Bach, Anders; Deshmukh, Atul Shahaji; Kilpeläinen, Tuomas O.; Strømgaard, Kristian; Madsen, Kenneth Lindegaard; Clemmensen, Christoffer.

In: Science Advances, Vol. 10, No. 9, eadg2636, 2024.

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

Harvard

Fadahunsi, N, Petersen, JO, Metz, S, Jakobsen, A, Mathiesen, CV, Buch-Rasmussen, AS, Kurgan, NK, Larsen, JK, Andersen, RC, Topilko, T, Svendsen, C, Apuschkin, M, Skovbjerg, G, Schmidt, JH, Houser, GA, Jager, SE, Bach, A, Deshmukh, AS, Kilpeläinen, TO, Strømgaard, K, Madsen, KL & Clemmensen, C 2024, 'Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment', Science Advances, vol. 10, no. 9, eadg2636. https://doi.org/10.1126/sciadv.adg2636

APA

Fadahunsi, N., Petersen, J. O., Metz, S., Jakobsen, A., Mathiesen, C. V., Buch-Rasmussen, A. S., Kurgan, N. K., Larsen, J. K., Andersen, R. C., Topilko, T., Svendsen, C., Apuschkin, M., Skovbjerg, G., Schmidt, J. H., Houser, G. A., Jager, S. E., Bach, A., Deshmukh, A. S., Kilpeläinen, T. O., ... Clemmensen, C. (2024). Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment. Science Advances, 10(9), [eadg2636]. https://doi.org/10.1126/sciadv.adg2636

Vancouver

Fadahunsi N, Petersen JO, Metz S, Jakobsen A, Mathiesen CV, Buch-Rasmussen AS et al. Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment. Science Advances. 2024;10(9). eadg2636. https://doi.org/10.1126/sciadv.adg2636

Author

Fadahunsi, Nicole ; Petersen, Jonas Odgaard ; Metz, Sophia ; Jakobsen, Alexander ; Mathiesen, Cecilie Vad ; Buch-Rasmussen, Alberte Silke ; Kurgan, Nigel Kilty ; Larsen, Jeppe Kjærgaard ; Andersen, Rita Chan ; Topilko, Thomas ; Svendsen, Charlotte ; Apuschkin, Mia ; Skovbjerg, Grethe ; Schmidt, Jan Hendrik ; Houser, Grace Anne ; Jager, Sara Elgaard ; Bach, Anders ; Deshmukh, Atul Shahaji ; Kilpeläinen, Tuomas O. ; Strømgaard, Kristian ; Madsen, Kenneth Lindegaard ; Clemmensen, Christoffer. / Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment. In: Science Advances. 2024 ; Vol. 10, No. 9.

Bibtex

@article{dfce2447cc0945449a63aa1a45df51a5,
title = "Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment",
abstract = "Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Loci in/near discs large homolog 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P < 5 × 10^−8) for BF% and/or BMI. To further evaluate the functional role of postsynaptic density protein-95 (PSD-95; gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PSD-95/disc large/ZO-1 (PDZ) domain–targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising therapeutic avenue for sustained weight loss.",
author = "Nicole Fadahunsi and Petersen, {Jonas Odgaard} and Sophia Metz and Alexander Jakobsen and Mathiesen, {Cecilie Vad} and Buch-Rasmussen, {Alberte Silke} and Kurgan, {Nigel Kilty} and Larsen, {Jeppe Kj{\ae}rgaard} and Andersen, {Rita Chan} and Thomas Topilko and Charlotte Svendsen and Mia Apuschkin and Grethe Skovbjerg and Schmidt, {Jan Hendrik} and Houser, {Grace Anne} and Jager, {Sara Elgaard} and Anders Bach and Deshmukh, {Atul Shahaji} and Kilpel{\"a}inen, {Tuomas O.} and Kristian Str{\o}mgaard and Madsen, {Kenneth Lindegaard} and Christoffer Clemmensen",
year = "2024",
doi = "10.1126/sciadv.adg2636",
language = "English",
volume = "10",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "9",

}

RIS

TY - JOUR

T1 - Targeting postsynaptic glutamate receptor scaffolding proteins PSD-95 and PICK1 for obesity treatment

AU - Fadahunsi, Nicole

AU - Petersen, Jonas Odgaard

AU - Metz, Sophia

AU - Jakobsen, Alexander

AU - Mathiesen, Cecilie Vad

AU - Buch-Rasmussen, Alberte Silke

AU - Kurgan, Nigel Kilty

AU - Larsen, Jeppe Kjærgaard

AU - Andersen, Rita Chan

AU - Topilko, Thomas

AU - Svendsen, Charlotte

AU - Apuschkin, Mia

AU - Skovbjerg, Grethe

AU - Schmidt, Jan Hendrik

AU - Houser, Grace Anne

AU - Jager, Sara Elgaard

AU - Bach, Anders

AU - Deshmukh, Atul Shahaji

AU - Kilpeläinen, Tuomas O.

AU - Strømgaard, Kristian

AU - Madsen, Kenneth Lindegaard

AU - Clemmensen, Christoffer

PY - 2024

Y1 - 2024

N2 - Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Loci in/near discs large homolog 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P < 5 × 10^−8) for BF% and/or BMI. To further evaluate the functional role of postsynaptic density protein-95 (PSD-95; gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PSD-95/disc large/ZO-1 (PDZ) domain–targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising therapeutic avenue for sustained weight loss.

AB - Human genome-wide association studies (GWAS) suggest a functional role for central glutamate receptor signaling and plasticity in body weight regulation. Here, we use UK Biobank GWAS summary statistics of body mass index (BMI) and body fat percentage (BF%) to identify genes encoding proteins known to interact with postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Loci in/near discs large homolog 4 (DLG4) and protein interacting with C kinase 1 (PICK1) reached genome-wide significance (P < 5 × 10^−8) for BF% and/or BMI. To further evaluate the functional role of postsynaptic density protein-95 (PSD-95; gene name: DLG4) and PICK1 in energy homeostasis, we used dimeric PSD-95/disc large/ZO-1 (PDZ) domain–targeting peptides of PSD-95 and PICK1 to demonstrate that pharmacological inhibition of PSD-95 and PICK1 induces prolonged weight-lowering effects in obese mice. Collectively, these data demonstrate that the glutamate receptor scaffolding proteins, PICK1 and PSD-95, are genetically linked to obesity and that pharmacological targeting of their PDZ domains represents a promising therapeutic avenue for sustained weight loss.

U2 - 10.1126/sciadv.adg2636

DO - 10.1126/sciadv.adg2636

M3 - Journal article

C2 - 38427737

VL - 10

JO - Science advances

JF - Science advances

SN - 2375-2548

IS - 9

M1 - eadg2636

ER -

ID: 384347826