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An estrogen receptor α-derived peptide improves glucose homeostasis during obesity

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE262841 | GEO | 2024/04/05

REPOSITORIES: GEO

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Project description:Background: The constitutively active ESR1 Y537S mutation is associated with endocrine therapy resistance and progression of metastatic breast cancer through its effects on estrogen receptor (ERα) gene regulatory functions. However, the complex relationship between ERα and the progesterone receptor (PR), known as ERα/PR crosstalk, has yet to be characterized in the context of the ERα Y537S mutation. This study aimed to elucidate the effects of the ERα Y537S mutation on ERα/PR crosstalk and resultant transcriptional activity and to identify potential therapeutic sensitivities that may offer novel treatment options to patients with endocrine therapy-resistant breast cancer. Methods: Proximity-based interactions of ERα and PR were assessed via proximity ligation assay (PLA). Gene expression in MCF7 and T47D cells was assessed by RNA-seq analysis with comparison to publicly available patient tumor transcriptome data. Chromatin immunoprecipitation (ChIP)-qPCR and immunoblotting were used to assess ERα/PR-associated gene expression and protein expression, respectively. Data were analyzed by ordinary two-way ANOVA (α = 0.05) with Tukey’s multiple comparisons tests. Results: Physical interaction of ERα and PR was increased in the context of the ERα Y537S mutation, including in the nucleus where this interaction may translate to altered gene expression. As such, more than 30 genes were differentially expressed in both patient tumor and cell line data (MCF7 and/or T47D cells) in the context of the ERα Y537S mutation compared to ERα WT. Of these, IRS1 stood out as a gene of interest, and ERα and PR occupancy at chromatin binding sites along IRS1 were uniquely altered in the context of ERα Y537S. Furthermore, siRNA knockdown of IRS1 or treatment with the IRS1 inhibitor NT-157 indicated a significant anti-proliferative effect of IRS1 depletion or inhibition in ERα Y537S cell lines. Conclusions: Previous research has characterized gene regulatory changes associated with the ERα Y537S mutation from the viewpoint of ERα. Here, we identify consequential changes to both ERα and PR transcription factor activity, including at chromatin binding sites for the signaling adaptor protein IRS1. We identified a significant dependence of ERα Y537S-expressing cells on IRS1 for proliferation, implicating IRS1 as a potential therapeutic target for restoring treatment sensitivity to patients with breast cancers harboring ERα Y537S mutations.

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An estrogen receptor α-derived peptide improves glucose homeostasis during obesity

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