Cytokine and Metabolic Regulation of Adipose-tissue Tregs

项目总结 在过去的几十年里，肥胖相关的代谢紊乱，包括胰岛素抵抗，2型 糖尿病和心血管疾病已经成为主要的健康负担，影响到多达四分之一的美国人。 成年人。内脏脂肪组织(VAT)的慢性低度炎症，最终导致 全身炎症，是肥胖引起的代谢异常的主要驱动因素。然而，这些机制 肥胖引起的炎症的发生和发展的机制仍然知之甚少。独一无二的 Foxp3+调节性T细胞(Tregs)具有独特的抗原受体谱系和转录 瘦雄性小鼠和雌激素缺乏雌性小鼠的VAT中的Profile积累，保持炎症 检查，并促进新陈代谢健康。然而，肥胖会显著减少增值税的税率和损失 它们的明显特征，导致炎症加剧和代谢结果恶化。这种肥胖- 诱导毒性严重阻碍VAT-Treg靶向抗代谢策略的发展 精神错乱。这个拟议项目的总体目标是使用新的遗传和生化工具来揭示 控制增值税动态平衡的独特细胞因子、代谢和性激素调节机制 Tregs处于稳定状态，并研究这些通路的中断如何导致肥胖诱导 增值税对男性和雌激素缺乏女性的毒性。通过追踪动态和转录 在饮食诱导的肥胖模型中，Tregs驻留在EVAT中的变化，我们发现 长期高脂饮食(HFD)喂养期间EVAT Tregs的减少与I型糖尿病的诱导有关 干扰素信号和参与胆固醇合成和吸收的转录本同时丢失。进一步 实验表明，EVAT树优先依赖于胆固醇稳态，而胆固醇稳态受 肥胖诱导的I型干扰素。此外，我们还发现雌性小鼠体内的VAT Tregs对肥胖有反应 在雌激素依赖的方式上与男性不同。基于这些观察，我们将澄清 控制VAT Treg动态平衡的机制及其通过三个特定目标对肥胖的反应： 在目标1中，我们将阐明I型IFN升高导致EVAT Tregs和EVAT Tregs下降的机制 促进肥胖期间的代谢异常。 在目标2中，我们将确定胆固醇稳态在EVAT树中的具体作用以及它的扰动 导致肥胖时EVAT-Tregs的失调。 在目标3中，我们将阐明VAT Tregs如何应对雌激素信号中断的女性肥胖。 这些努力将支持我们更好地了解驱动免疫的机制的长期目标 肥胖相关慢性病的调节失调。

PROJECT SUMMARY Over the last few decades, obesity-associated metabolic disorders, including insulin resistance, type-2 diabetes, and cardiovascular diseases, have become a major health burden, affecting up to a quarter of U.S. adults. Chronic, low-grade inflammation of the visceral adipose tissue (VAT), which eventually leads to systemic inflammation, is a major driver of obesity-induced metabolic abnormalities. However, the mechanisms of the initiation and progression of obesity-induced inflammation are still poorly understood. A unique population of Foxp3+ regulatory T cells (Tregs) with a distinct antigen receptor repertoire and transcriptional profile accumulates in VAT of lean male mice and estrogen-deficient female mice, keeps the inflammation in check, and promotes metabolic health. Obesity, however, leads to significant reduction of VAT Tregs and loss of their distinct features, resulting in elevated inflammation and worsened metabolic outcomes. This obesity- induced toxicity severely hinders the development of VAT-Treg-targeted strategies against metabolic disorders. The overall goal of this proposed project is to use novel genetic and biochemical tools to uncover the unique cytokine, metabolic, and sex-hormone-mediated mechanisms that control the homeostasis of VAT Tregs at steady state, and to investigate how disruption of these pathways could contribute to obesity-induced toxicity of VAT Tregs in both males and estrogen-deficient females. By tracing the dynamics and transcriptomic changes of Tregs residing in the epidydimal VAT (eVAT) in a diet-induced obesity model, we identified that the reduction of eVAT Tregs during long-term high-fat-diet (HFD) feeding is associated with induction of a type I IFN signature and a concurrent loss of transcripts involved in the synthesis and uptake of cholesterol. Further experiments showed that eVAT Tregs preferentially depend on cholesterol homeostasis, which is inhibited by obesity-induced type I IFNs. In addition, we identified that VAT Tregs from female mice respond to obesity differently from males in an estrogen-dependent manner. Building on these observations, we will elucidate the mechanisms that control VAT Treg homeostasis and their response to obesity through three specific aims: In Aim 1, we will elucidate the mechanisms by which elevated type I IFNs drive the decline of eVAT Tregs and promote metabolic abnormalities during obesity. In Aim 2, we will determine the specific role of cholesterol homeostasis in eVAT Tregs and how its perturbation contributes to the dysregulation of eVAT Tregs during obesity. In Aim 3, we will elucidate how VAT Tregs respond to obesity in females with disrupted estrogen signaling. These efforts will support our long-term goal to better understand the mechanisms that drive immune dysregulation in obesity-associated chronic diseases.