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