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Estrogen Receptor α Protects Against Obesity-Induced Metabolic Dysfunction by Regulating VAT Tregs (oVAT)

ABSTRACT: Estrogens are important for metabolic health. Individuals with low levels of circulating estrogens, including men and postmenopausal women, exhibit an elevated risk for developing obesity-associated metabolic syndromes. Chronic low-grade inflammation in the visceral adipose tissue (VAT) is a major contributor to metabolic dysfunction during obesity. Regulatory T cells (Tregs) in the VAT limit tissue inflammation and protect against obesity-associated metabolic disease. In this study, we identify opposing roles of estrogen receptor α (ERα) in regulating VAT Tregs in female mice under steady-state and obese conditions. At steady state, ERα restrained the age-dependent clonal expansion of specific VAT Treg subsets expressing the IL-33 receptor ST2. However, during obesity, ERα-deficiency predisposed females to the loss of ST2+ VAT Tregs, exacerbating VAT inflammation and insulin resistance. These findings indicate that ERα signaling protects against obesity-induced metabolic diseases by preserving metabolically protective ST2+ VAT Treg subsets, and the loss of this protection may contribute to the heightened metabolic risk in estrogen-deficient individuals.

ORGANISM(S): Mus musculus

PROVIDER: GSE312696 | GEO | 2026/02/13

REPOSITORIES: GEO

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Estrogen Receptor α Protects Against Obesity-Induced Metabolic Dysfunction by Regulating VAT Tregs

Project description:Estrogens are important for metabolic health. Individuals with low levels of circulating estrogens, including men and postmenopausal women, exhibit an elevated risk for developing obesity-associated metabolic syndromes. Chronic low-grade inflammation in the visceral adipose tissue (VAT) is a major contributor to metabolic dysfunction during obesity. Regulatory T cells (Tregs) in the VAT limit tissue inflammation and protect against obesity-associated metabolic disease. In this study, we identify opposing roles of estrogen receptor α (ERα) in regulating VAT Tregs in female mice under steady-state and obese conditions. At steady state, ERα restrained the age-dependent clonal expansion of specific VAT Treg subsets expressing the IL-33 receptor ST2. However, during obesity, ERα-deficiency predisposed females to the loss of ST2+ VAT Tregs, exacerbating VAT inflammation and insulin resistance. These findings indicate that ERα signaling protects against obesity-induced metabolic diseases by preserving metabolically protective ST2+ VAT Treg subsets, and the loss of this protection may contribute to the heightened metabolic risk in estrogen-deficient individuals.

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Gene expression of visceral adipose regulatory T cells from mice with specific deletion of insulin receptor in the cells

Project description:Visceral adipose tissue (VAT) regulatory T cells (Tregs) control inflammation and metabolism. Diet-induced obesity causes hyperinsulinemia and diminishes VAT Treg number and function, but whether these two phenomena were mechanistically linked was unknown. We hypothesized that excessive insulin signaling in obesity negatively impact VAT Tregs. Using Treg-specific insulin receptor deletion (Foxp3-cre;Insr-fl/fl) mice, we compared the gene expression of VAT Tregs from control and knockout mice in obesity and aging, two models of hyperinsulinemia. We found that genes associated with Treg functions were altered in Tregs lacking insulin receptor.

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The impact of IL-33 on Srebf2-dependent cholesterol gene expression in ST2+ eVAT Tregs

Project description:Tregs are highly enriched in the eVAT of male mice. We show that ST2+ VAT Tregs preferentially upregulate and depend on Srebf2-mediated cholesterol metabolism compared their spleen Treg or ST2- VAT Treg counterparts. However, it is unclear whether this increased reliance on cholesterol metabolism is a consequence elevated IL-33 signaling in ST2+ Tregs. Therefore, the goal of experiment is to determine whether IL-33 signaling influences Srebf2-dependent cholesterol gene expression in ST2+ eVAT Tregs in vivo.

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Inflammation-dependent differentiation of two distinct regulatory T cell populations in the visceral adipose tissue shapes systemic metabolism [RNA-seq I]

Project description:Visceral adipose tissue (VAT) is an endocrine organ critical for energy storage and metabolic homeostasis. Its function, at least in part, is controlled by immune cells, including Foxp3+ regulatory T (Treg) cells, which restrain VAT inflammation and glucose intolerance. Here we uncover that the VAT harbours two distinct Treg cell populations, prototypical ST2+ Treg cells, that are enriched in males and depend on the cytokine IL-33 and the transcription factor PPAR and a previously uncharacterized population of VAT Treg cells that express the chemokine receptor CXCR3+, are enriched in females and depend on the transcription factor T-bet. We further show that the transcription factor GATA3 promoted differentiation of ST2+ VAT Treg cells and together with PPAR and IL-33 repressed the differentiation of CXCR3+ Treg cells. CXCR3+ VAT Treg cells developed from naïve Treg cells in a cytokine IFN- dependent manner. Finally, we demonstrate that ST2+ Treg cells promoted glucose tolerance, while CXCR3+ Treg cells limited VAT inflammation in a sex specific manner. This study for the first time establishes how inflammation determines the developmental trajectories of two functionally and molecularly distinct Treg cell types in the VAT.

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Inflammation-dependent differentiation of two distinct regulatory T cell populations in the visceral adipose tissue shapes systemic metabolism [RNA-seq III]

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Inflammation-dependent differentiation of two distinct regulatory T cell populations in the visceral adipose tissue shapes systemic metabolism [RNA-seq II]

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Project description:Foxp3+ regulatory T cells (Tregs) are critical mediators of peripheral tolerance and immune homeostasis. Tregs that express the IL-33 receptor ST2 are enriched in peripheral nonlymphoid tissues and can exert a variety of tissue-specific functions from metabolic regulation within adipose tissue to skeletal muscle repair. However, the relationship between ST2+ and ST2- Tregs within and across different tissues remains unclear. To compare murine ST2- and ST2+ Tregs within and across tissues, we performed RNA sequencing (RNAseq) of ST2-CD44hi and ST2+CD44hi Tregs from blood, spleen, lungs, visceral adipose tissue (VAT), colon, and skin. RNAseq was also performed on ST2- CD44lo CD62L+ Tregs from the spleen and lungs. We found that the tissue microenvironment was the major factor shaping the transcriptome of Tregs across tissues. Across the tissues studied, Treg transcriptomes displayed an ordered hierarchy that may represent graded levels of activation or differentiation across tissues. We also identified a core signature that distinguished ST2+ Tregs from ST2- Tregs across tissues and a large number of differentially expressed genes between ST2- and ST2+ Tregs within individual tissues that could support the tissue-specific adaptation and function of ST2+ Tregs. In summary, our work highlights the unique, tissue-specific phenotype of ST2+ Tregs and reveals a core ST2+ Treg transcriptional signature shared across tissues.

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Single cell transcriptomic analysis (InDrops) of mouse mesenchymal stromal cells (mSCs or FAPs, fibro-adipogenic progenitors) isolated from lymph node, muscle and visceral adipose tissue

Project description:Regulatory T cells (Tregs) are key brakes on the VAT inflammation that regulates local and systemic metabolic tenor. The cytokine, IL-33, expands and sustains the unique Treg population residing within VAT. Making use of single-cell RNA sequencing, we identified the major IL-33 producers in VAT to be particular mSC subtypes, related to but distinct from adipocyte progenitor cells. We further characterize these subsets by individually isolating them and performing bulk-RNA sequencing. We explored modulation of the VAT-mSC (VmSC) landscape with physiologic variables such as age and sex, as well as pathogenic states like obesity. We uncovered a VAT Treg:stromal-cell negative regulatory loop that keeps the potent effect of IL-33 under rein.

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