Therapeutic PYY/GLP-1 receptor co-agonism in obese-diabetic mice
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ABSTRACT:
PROVIDER: PRJNA674568 | ENA |
REPOSITORIES: ENA
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Project description:Therapeutic PYY/GLP-1 receptor co-agonism in obese-diabetic mice synergistically activates discrete hypothalamic and brainstem neuronal circuitries for weight reduction, increased insulin sensitization, recovery of pancreatic ß-cell function and diabetes remission. GLP1-R agonism (IP118) and PYY-2R agonism (PY115) in combination yield surprising synergistic effects on energy homeostasis in mammals. To better understand the genesis of these effects, RNAseq profiling was performed on key brain regions following an acute dose of IP118+PY115.
2021-03-01 | GSE160802 | GEO
Project description:Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor agonist, has been shown to deliver enhanced glycemic control and superior weight loss compared to a selective GLP-1 receptor (GLP-1R) agonist in patients with type 2 diabetes mellitus. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes to the therapy is not fully understood. Here, hyperinsulinemic-euglycemic clamp studies were used to show that tirzepatide is a highly effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine if GIPR agonism contributes to the insulin sensitization, we compared the effect of tirzepatide in obese wild-type and Glp-1r null mice. In the absence of GLP-1R induced weight loss, tirzepatide improved systemic insulin sensitivity by enhancing glucose disposal in WAT. To corroborate these results, chronic treatment with a long-acting GIPR agonist (LAGIPRA) was also found to enhance insulin sensitivity by increasing insulin stimulated glucose uptake in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched chain amino and keto acids in the circulation. Whole-body insulin sensitization was associated with pronounced upregulation of genes associated with the catabolism of glucose, lipid and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual GIP and GLP-1 receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
2021-04-29 | GSE173522 | GEO
Project description:We investigate the effects of GLP-1 on diabetic cardiomyocytes (DCMs) model established by human induced pluripotent stem cells-derived cardiomyocytes (iPSC-CMs). Two subtypes of GLP-1, GLP-17-36 and GLP-19-36, were evaluated for their efficacy on hypertrophic phenotype, impaired calcium homeostasis and electrophysiological properties. RNA-seq was performed to reveal the underlying molecular mechanism of GLP-1. Our results demonstrated that GLP-17-36 and GLP-19-36 were able to ameliorate high glucose-induced hypertrophy phenotype and cardiac dysfunctions in DCM model based on iPSC-CMs. Our study provides a novel platform to unveil the cellular mechanisms of diabetic cardiomyopathy, which sheds light on discovering better targets for novel therapeutic interventions.
2022-07-01 | GSE197850 | 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.
2024-04-26 | PXD045816 | Pride
Project description:Combinatorial therapies are under intense investigation for the development of more efficient anti-obesity drugs, however little is known about how they act in brain to produce enhanced satiety and weight loss. Here we used a multidisciplinary strategy to decipher the central mechanisms engaged downstream from the co-administration of GLP-1R and CCK1R agonists, an efficient combination therapy in obese rodents. The nucleus of the solitary tract (NTS) contained one of the few neuronal populations synergistically activated in response to GLP-1R and CCK1R co-agonism. None of the previously categorized NTS neuronal subpopulations relevant to feeding behaviour were synergistically activated. However, using PhosphoTRAP, we obtained the molecular signature of NTS and ARH neurons synergistically regulated by the GLP-1R and CCK1R co-agonism and identified NTS/AP Calcrl+ neurons and ARH Adcyap1r1+ neurons as targets of this treatment. Collectively these studies advance our understanding of the central mechanisms involved in the synergistic appetite- and weight-suppressive effect of a combinatorial therapy.
2019-08-16 | GSE135862 | GEO
Project description:Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective treatments for type 2 diabetes, effectively lowering glucose without weight gain and with low risk for hypoglycemia. However, their influence on the retinal neurovascular unit remains unclear. In this study we analyzed the effects of the GLP-1 RA lixisenatide in a rat model of type-1 like diabetic retinopathy. Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats acellular capillaries and pericytes (quantitative retinal morphometry), neuroretinal function (mfERG), macroglia (GFAP western blot) and microglia (immunohistochemistry) quantification, methylglyoxal (LC-MS/MS) and retinal gene expressions (RNA-sequencing) were determined. The antioxidant properties of lixisenatide were tested in C. elegans. Lixisenatide had no effect on glucose metabolism. Lixisenatide preserved the retinal vasculature and neuroretinal function. The macro- and microglial activation was mitigated. Lixisenatide normalized some gene expression changes in diabetic animals to control levels. Ets2 was identified as a regulator of inflammatory genes. In C. elegans lixisenatide showed the antioxidative property. In summary, these data suggest that lixisenatide has a protective effect on the diabetic retina, most likely due to a combination of neuroprotective, anti-inflammatory and antioxidative effects of lixisenatide on the neurovascular unit.
2023-07-05 | GSE236333 | GEO
Project description:Obesity and type 2 diabetes (T2D) can be associated with altered secretion of enterohormones in condition that remains to be understood in depth. Here, we aimed to decipher the mechanisms by which a major enterohormone GLP-1, is decreased in human obese patients according to their diabetic status.
2020-10-19 | GSE132831 | GEO
Project description:Type 2 diabetes is a complex disease associated with many underlying pathomechanisms. Epigenetic regulation of gene expression by DNA methylation has become increasingly recognized as an important component in the etiology of type 2 diabetes. We performed genome-wide methylome and transcriptome analysis in liver from severely obese patients with or without type 2 diabetes to discover aberrant pathways underlying the development of insulin resistance. We identified hypomethylation of five key genes involved in hepatic glycolysis, de novo lipogenesis and insulin resistance with concomitant increased mRNA expression and protein content. The CpG-site within the ATF-motif was hypomethylated in four of these genes in liver of non-diabetic and type 2 diabetic obese patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. In conclusion, severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome and genes controlling glucose and lipid metabolism are hypomethylated at a regulatory site. Thus, obesity may epigenetically reprogram the liver towards increased lipid production and exacerbate the development of insulin resistance. To better understand the molecular mechanisms underlying the development of hepatic insulin resistance and type 2 diabetes at a molecular level, we performed a genome-wide methylome and transcriptome analysis of liver from non-obese metabolically healthy, obese non-diabetic and obese type 2 diabetic patients. Distinct DNA methylation and gene expression profiles were identified in liver from the obese and type 2 diabetic patients compared with the non-obese participants.
2016-03-08 | E-GEOD-64998 | biostudies-arrayexpress
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: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