GLP-1 directed NMDA receptor antagonism for obesity treatment [II]
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ABSTRACT:
PROVIDER: PRJNA1029627 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description: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.
2024-04-26 | PXD045816 | Pride
Project description: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.
2024-05-14 | GSE244607 | GEO
Project description: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.
2024-05-14 | GSE245727 | GEO
Project description:GLP-1 directed NMDA receptor antagonism for obesity treatment
| PRJNA1029620 | ENA
Project description:GLP-1 directed NMDA receptor antagonism for obesity treatment [I]
| PRJNA1023883 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-05-14 | GSE245728 | GEO
Project description:AIM: to examine changes in hypothalamic gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. AIM: to examine changes in hypothalamic gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. This data will compliment on-going studies into the effect of developmental NMDA receptor antagonism on aspects of the Hypothalamic-Pituitary-Adrenal (HPA) axis.
2019-12-13 | GSE108042 | GEO
Project description:AIM: to examine changes in adrenal gene expression following developmental N-Methyl D-aspartate (NMDA) receptor antagonism in adult female C57Bl/6J mice. This data will compliment on-going studies into the effect of developmental NMDA receptor antagonism on aspects of the Hypothalamic-Pituitary-Adrenal (HPA) axis.
2019-12-13 | GSE108032 | GEO
Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.
2022-09-23 | GSE184055 | GEO
Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.
2022-09-23 | GSE184261 | GEO