open access publication

Article, 2024

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

Science Advances, ISSN 2375-2548, Volume 10, 9, Page eadg2636, 10.1126/sciadv.adg2636

Contributors

Fadahunsi, Nicole [1] Petersen, Jonas O 0000-0002-6219-0271 [1] Metz, Sophia [1] Jakobsen, Alexander [1] Mathiesen, Cecilie Vad 0000-0002-8325-5898 [1] Buch-Rasmussen, Alberte Silke 0000-0001-6538-8059 [1] [2] Kurgan, Nigel Kilty 0000-0002-5011-0297 [1] Larsen, Jeppe Kjærgaard 0000-0002-9304-1148 [1] Andersen, Rita Chan 0000-0003-3025-5007 [1] Topilko, Thomas [3] Svendsen, Charlotte Sashi Aier 0000-0002-8329-319X [1] Apuschkin, Mia 0000-0003-3942-2174 [1] Skovbjerg, Grethe 0009-0001-4054-987X [1] [3] Schmidt, Jan Hendrik [1] Houser, Grace 0009-0004-8144-8719 [1] Jager, Sara Elgaard 0000-0002-2480-0024 [1] Bach, Anders 0000-0003-4305-9910 [1] Deshmukh, Atul Shahaji 0000-0002-2278-1843 [1] Kilpeläinen, Tuomas O 0000-0002-8349-3028 [1] Strømgaard, Kristian 0000-0003-2206-4737 [1] Madsen, Kenneth Lindegaard 0000-0001-9274-6691 [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] Novo Nordisk (Denmark)
    3. [NORA names: Novo Nordisk; Private Research; Denmark; Europe, EU; Nordic; OECD];
  3. [3] Gubra (Denmark)
    4. [NORA names: Gubra; Private Research; Denmark; Europe, EU; Nordic; OECD]

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.

Keywords

AMPA, C kinase 1, Disks large homolog 4, GWAS summary statistics, Loci, PDZ domain, PICK1, PSD-95, PSD-95/discs large/ZO-1, UK Biobank GWAS summary statistics, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, acid, association studies, avenues, body, body fat percentage, body mass index, body weight regulation, data, domain, effect, energy, energy homeostasis, fat percentage, functional role, genes, genome-wide association studies, genome-wide significance, glutamate, glutamate receptor signaling, homeostasis, homolog 4, human genome-wide association studies, index, loss, mass index, mice, obese mice, obesity, obesity treatment, percentage, pharmacological inhibition, pharmacological targets, plasticity, postsynaptic density protein 95, protein, protein PSD-95, receptor signaling, regulation, role, scaffold protein, scaffolding protein PSD-95, signal, significance, statistically, study, summary statistics, sustained weight loss, target, therapeutic avenues, treatment, weight loss, weight regulation, weight-lowering effects

Funders

  • Lundbeck Foundation
  • Novo Nordisk Foundation
  • Novo Nordisk (Denmark)
  • Lundbeck (Denmark)

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