An estrogen receptor α-derived peptide improves glucose homeostasis during obesity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1093463 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28503470_1.fastq.gz | Fastqsanger.gz | |||
| SRR28503470_2.fastq.gz | Fastqsanger.gz | |||
| SRR28503471_1.fastq.gz | Fastqsanger.gz | |||
| SRR28503471_2.fastq.gz | Fastqsanger.gz | |||
| SRR28503472_1.fastq.gz | Fastqsanger.gz |
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Project description:Estrogen improves insulin sensitivity and increases energy expenditure, contributing to sexual dimorphism regarding type 2 diabetes mellitus (T2DM) susceptibility. Estrogen receptor α (ERα) plays a crucial role in mediating estrogen action on glucose and energy homeostasis. However, the underlying mechanisms remain incompletely understood. Here, we found a ligand-independent effect of ERα on the regulation of glucose homeostasis and identified an ERα-derived peptide as a potential insulin sensitizer. Deficiency of ERα but not ERβ in the liver impaired glucose homeostasis in male, female, and ovariectomized (OVX) female mice. Mechanistic studies revealed that ERα promoted hepatic insulin sensitivity by suppressing ubiquitination-induced IRS1 degradation. The ERα 1-280 domain mediated the ligand-independent effect of ERα on insulin sensitivity. Furthermore, we designed a peptide based on ERα 1-280 domain and found that ERα-derived peptide interacted with IRS1, increased IRS1 stability through suppressing its ubiquitination, and enhanced insulin sensitivity. Importantly, administration of ERα-derived peptide into obese mice significantly increased insulin sensitivity, attenuated glucose intolerance, and improved serum lipid profiles. These findings pave the way for the therapeutic intervention of T2DM by targeting the ligand-independent effect of ERα and indicate that ERα-derived peptide is a potential insulin sensitizer for the treatment of T2DM.
2024-04-05 | GSE262841 | GEO
Project description:Irisin is secreted by muscle, increased with exercise, and conveys certain physiological benefits. Earlier studies showed that short-term irisin treatment caused browning of subcutaneous adipose tissue (SAT) in mice, with improved glucose tolerance; the effects of more chronic irisin treatment and mechanisms at play have not been explored. We demonstrate here that chronic irisin application improves obesity and dramatically reduces glucose intolerance. This treatment increases an IL-33+ mesenchymal stromal cell (mSC) population in visceral fat tissue while genetic ablation of irisin reduces plasma IL-33 levels and decreases thermogenic gene expression in SAT. Importantly, irisin directly induces IL-33 expression in mSCs and preserves ST2+ regulatory T (Treg) cells. Inhibition of IL-33 blunts these irisin-mediated effects on energy expenditure and glucose homeostasis, largely through IL33-mediated regulation of ST2+ Treg cells. These data indicate that irisin improves obesity and glucose intolerance, with no muscle loss, through a key immunomodulatory pathway in obese mice.
2025-12-05 | GSE283234 | GEO
Project description:Irisin is secreted by muscle, increased with exercise, and conveys certain physiological benefits. Earlier studies showed that short-term irisin treatment caused browning of subcutaneous white fat in mice, with improved glucose tolerance; the effects of more chronic irisin treatment and mechanisms at play have not been explored. We demonstrate here that chronic irisin application improves obesity and dramatically reduces glucose intolerance. This treatment increases an IL-33+ mesenchymal stromal cell (mSC) population, while genetic ablation of irisin reduces plasma IL-33 levels and decreases thermogenic gene expression in subcutaneous adipose tissue. Importantly, irisin directly induces IL-33 expression in mSCs and stimulates ST2+regulatory T (Treg) cells, inducing their tissue accumulation. Inhibition of IL-33 blunts these irisin-mediated effects on energy expenditure and glucose homeostasis, largely through IL33-mediated regulation of ST2+ Treg cells. These data indicate that irisin improves obesity and glucose intolerance, with no muscle loss, through a key immunomodulatory pathway in obese mice .
2026-01-15 | GSE282942 | GEO
Project description:Background: Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Methods: We combined mouse genetics, electrophysiology, neural tracing, optogenetics and Patch-RNA-seq to demonstrate how glucose-sensing neurons in the ventrolateral VMH regulate glucose balance. Results: Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) are glucose-sensing neurons to a 5-1-5mM glucose fluctuation, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH-mpARH circuit and inhibition of ERαvlVMH-DRN circuit both increase blood glucose. Conclusions: Our results indicate that ERαvlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.
2020-04-01 | GSE146543 | GEO
Project description:Rationale: Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate receptors ERα and ERβ. Since female sex hormones enhance global glucose utilization and because myocardial function and mass are tightly linked to cardiac glucose metabolism we tested the hypothesis that expression and activation of the estrogen receptor α (ERα) might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Methods and Results: Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was strongly impaired in ovarectomized compared to gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the non-selective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovarectomized mice. Cardiac FDG uptake was strongly decreased in female ERα knockout mice (ERKO) compared to wild type littermates. Biochemical assays, affymetrix cDNA array analysis, western blotting and immuno-staining of cardiac glucose transporters revealed a positive correlation of ERα dependent cardiac FDG uptake with preserved cardiac glucose transporter-1 expression and micro-vascular localization. Conclusions: Systemic activation of the ERα estrogen receptor is sufficient and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardio-protective estrogen effects.
2012-12-20 | GSE34807 | GEO
Project description:Rationale: Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate receptors ERα and ERβ. Since female sex hormones enhance global glucose utilization and because myocardial function and mass are tightly linked to cardiac glucose metabolism we tested the hypothesis that expression and activation of the estrogen receptor α (ERα) might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Methods and Results: Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) was strongly impaired in ovarectomized compared to gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the non-selective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovarectomized mice. Cardiac FDG uptake was strongly decreased in female ERα knockout mice (ERKO) compared to wild type littermates. Biochemical assays, affymetrix cDNA array analysis, western blotting and immuno-staining of cardiac glucose transporters revealed a positive correlation of ERα dependent cardiac FDG uptake with preserved cardiac glucose transporter-1 expression and micro-vascular localization. Conclusions: Systemic activation of the ERα estrogen receptor is sufficient and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardio-protective estrogen effects. total samples analysed are 20
2012-12-20 | E-GEOD-34807 | biostudies-arrayexpress
Project description:Adjudin improves beta cell maturation, hepatic glucose uptake and glucose homeostasis
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Project description:We and others have proposed that coactivator binding inhibitors, which block the interaction of estrogen receptor and steroid receptor coactivators, may represent a potential class of new breast cancer therapeutics. The development of coactivator binding inhibitors has been limited, however, because many of the current molecules which are active in in vitro and biochemical assays are not active in cell-based assays. Our goal in this work was to prepare a coactivator binding inhibitor active in cellular models of breast cancer. To accomplish this, we used molecular dynamics simulations to convert a high-affinity stapled peptide with poor cell permeability into R4K1, a cell-penetrating stapled peptide. R4K1 displays high binding affinity for estrogen receptor ɑ, inhibits the formation of estrogen receptor/coactivator complexes, and distributes throughout the cell with a high percentage of nuclear localization. R4K1 represses native gene transcription mediated by estrogen receptor ɑ and inhibits proliferation of estradiol-stimulated MCF-7 cells. Using RNA-Seq, we demonstrate that almost all of the effects of R4K1 on global gene transcription are estrogen receptor-associated. This chemical probe provides a significant proof-of-concept for preparing cell-permeable stapled peptide inhibitors of the estrogen receptor/coactivator interaction.
2018-01-09 | GSE108308 | GEO
Project description:Irisin improves obesity and glucose intolerance through an IL-33-ST2 pathway
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Project description:Irisin improves obesity and glucose intolerance through an IL-33-ST2 pathway
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