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Series GSE244607 Query DataSets for GSE244607
Status Public on May 14, 2024
Title GLP-1 directed NMDA receptor antagonism for obesity treatment [I]
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
 
Overall design Comparative gene expression profiling analysis of RNA-seq data from brain stem and nucleus accumbens of mice which had been randomized to one of four treatment groups (Vehicle, MK-801, GLP-1 or MK-801/GLP-1). 8 replicates are sequenced for each tissue and treatment combination.
 
Contributor(s) 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 J, Finan B, Portillo B, Grose K, Petersen JE, Trauelsen M, Feuchtinger A, DiMarchi RD, Schwartz TW, Desmukh AS, Thomsen MB, Kohlmeier KA, Williams KW, Pers TH, Frølund B, Strømgaard K, Klein AB, Clemmensen C
Citation(s) 38750368
Submission date Oct 04, 2023
Last update date Jun 07, 2024
Contact name Lars Roed Ingerslev
E-mail(s) ingerslev@sund.ku.dk
Organization name Copenhagen University
Department NNF Center for Basic Metabolic Research
Lab Integrative Physiology
Street address Blegdamsvej 3B
City Copenhagen
ZIP/Postal code 2200
Country Denmark
 
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (64)
GSM7821809 Brain stem, Vehicle, rep1
GSM7821810 Brain stem, Vehicle, rep2
GSM7821811 Brain stem, Vehicle, rep3
This SubSeries is part of SuperSeries:
GSE245728 GLP-1 directed NMDA receptor antagonism for obesity treatment
Relations
BioProject PRJNA1023883

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Supplementary file Size Download File type/resource
GSE244607_salmon.merged.gene_counts.tsv.gz 3.5 Mb (ftp)(http) TSV
GSE244607_salmon.merged.transcript_counts.tsv.gz 14.7 Mb (ftp)(http) TSV
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Raw data are available in SRA

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