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| 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
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| 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.
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| 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.
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| 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 |
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| Submission date |
Oct 04, 2023 |
| Last update date |
Jun 07, 2024 |
| Contact name |
Lars Roed Ingerslev |
| E-mail(s) |
ingerslev@sund.ku.dk
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| Organization name |
Copenhagen University
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| Department |
NNF Center for Basic Metabolic Research
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| Lab |
Integrative Physiology
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| Street address |
Blegdamsvej 3B
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| City |
Copenhagen |
| ZIP/Postal code |
2200 |
| Country |
Denmark |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (64)
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| GSM7821812 |
Brain stem, Vehicle, rep4 |
| GSM7821813 |
Brain stem, Vehicle, rep5 |
| GSM7821814 |
Brain stem, Vehicle, rep6 |
| GSM7821815 |
Brain stem, Vehicle, rep7 |
| GSM7821816 |
Brain stem, Vehicle, rep8 |
| GSM7821817 |
Brain stem, MK-801, rep1 |
| GSM7821818 |
Brain stem, MK-801, rep2 |
| GSM7821819 |
Brain stem, MK-801, rep3 |
| GSM7821820 |
Brain stem, MK-801, rep4 |
| GSM7821821 |
Brain stem, MK-801, rep5 |
| GSM7821822 |
Brain stem, MK-801, rep6 |
| GSM7821823 |
Brain stem, MK-801, rep7 |
| GSM7821824 |
Brain stem, MK-801, rep8 |
| GSM7821825 |
Brain stem, GLP-1, rep1 |
| GSM7821826 |
Brain stem, GLP-1, rep2 |
| GSM7821827 |
Brain stem, GLP-1, rep3 |
| GSM7821828 |
Brain stem, GLP-1, rep4 |
| GSM7821829 |
Brain stem, GLP-1, rep5 |
| GSM7821830 |
Brain stem, GLP-1, rep6 |
| GSM7821831 |
Brain stem, GLP-1, rep7 |
| GSM7821832 |
Brain stem, GLP-1, rep8 |
| GSM7821833 |
Brain stem, GLP-1/MK-801, rep1 |
| GSM7821834 |
Brain stem, GLP-1/MK-801, rep2 |
| GSM7821835 |
Brain stem, GLP-1/MK-801, rep3 |
| GSM7821836 |
Brain stem, GLP-1/MK-801, rep4 |
| GSM7821837 |
Brain stem, GLP-1/MK-801, rep5 |
| GSM7821838 |
Brain stem, GLP-1/MK-801, rep6 |
| GSM7821839 |
Brain stem, GLP-1/MK-801, rep7 |
| GSM7821840 |
Brain stem, GLP-1/MK-801, rep8 |
| GSM7821841 |
Accumbens, Vehicle, rep1 |
| GSM7821842 |
Accumbens, Vehicle, rep2 |
| GSM7821843 |
Accumbens, Vehicle, rep3 |
| GSM7821844 |
Accumbens, Vehicle, rep4 |
| GSM7821845 |
Accumbens, Vehicle, rep5 |
| GSM7821846 |
Accumbens, Vehicle, rep6 |
| GSM7821847 |
Accumbens, Vehicle, rep7 |
| GSM7821848 |
Accumbens, Vehicle, rep8 |
| GSM7821849 |
Accumbens, MK-801, rep1 |
| GSM7821850 |
Accumbens, MK-801, rep2 |
| GSM7821851 |
Accumbens, MK-801, rep3 |
| GSM7821852 |
Accumbens, MK-801, rep4 |
| GSM7821853 |
Accumbens, MK-801, rep5 |
| GSM7821854 |
Accumbens, MK-801, rep6 |
| GSM7821855 |
Accumbens, MK-801, rep7 |
| GSM7821856 |
Accumbens, MK-801, rep8 |
| GSM7821857 |
Accumbens, GLP-1, rep1 |
| GSM7821858 |
Accumbens, GLP-1, rep2 |
| GSM7821859 |
Accumbens, GLP-1, rep3 |
| GSM7821860 |
Accumbens, GLP-1, rep4 |
| GSM7821861 |
Accumbens, GLP-1, rep5 |
| GSM7821862 |
Accumbens, GLP-1, rep6 |
| GSM7821863 |
Accumbens, GLP-1, rep7 |
| GSM7821864 |
Accumbens, GLP-1, rep8 |
| GSM7821865 |
Accumbens, GLP-1/MK-801, rep1 |
| GSM7821866 |
Accumbens, GLP-1/MK-801, rep2 |
| GSM7821867 |
Accumbens, GLP-1/MK-801, rep3 |
| GSM7821868 |
Accumbens, GLP-1/MK-801, rep4 |
| GSM7821869 |
Accumbens, GLP-1/MK-801, rep5 |
| GSM7821870 |
Accumbens, GLP-1/MK-801, rep6 |
| GSM7821871 |
Accumbens, GLP-1/MK-801, rep7 |
| GSM7821872 |
Accumbens, GLP-1/MK-801, rep8 |
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| This SubSeries is part of SuperSeries: |
| GSE245728 |
GLP-1 directed NMDA receptor antagonism for obesity treatment |
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| Relations |
| BioProject |
PRJNA1023883 |
| 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 |
SRA Run Selector |
| Raw data are available in SRA |
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