Cytokine and Metabolic Regulation of Adipose-tissue Tregs

项目摘要 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， 糖尿病和心血管疾病已经成为主要的健康负担，影响了美国四分之一的人口。 成年人了内脏脂肪组织（VAT）的慢性低度炎症，最终导致 全身性炎症是肥胖诱导的代谢异常的主要驱动因素。然而，机制 肥胖引起的炎症的发生和发展的机制仍然知之甚少。一个独特 Foxp 3+调节性T细胞（TCRs）群体具有不同的抗原受体库和转录 在瘦的雄性小鼠和雌激素缺乏的雌性小鼠的VAT中， 检查，并促进新陈代谢的健康。然而，肥胖导致VAT THBG和损失的显著减少 它们的独特特征，导致炎症升高和代谢结果恶化。肥胖症- 诱导的毒性严重阻碍了VAT-Treg靶向策略的发展， 紊乱该项目的总体目标是使用新的遗传和生物化学工具来揭示 独特的细胞因子，代谢和性激素介导的机制，控制VAT的稳态 在稳态下，研究这些通路的中断如何有助于肥胖诱导的 在雄性和雌激素缺乏的雌性动物中，VAT TdR的毒性。通过追踪动态和转录组学 在饮食诱导的肥胖模型中，我们发现， 长期高脂饮食（HFD）喂养期间eVAT TdR的降低与I型糖尿病的诱导相关。 干扰素签名和参与胆固醇合成和摄取的转录物的同时损失。进一步 实验表明，eVAT TdR优先依赖于胆固醇稳态，胆固醇稳态被 肥胖诱导的I型干扰素此外，我们还发现，雌性小鼠的VAT T细胞对肥胖有反应， 与男性不同，以雌激素依赖的方式。基于这些观察，我们将阐明 通过三个具体目标控制VAT Treg稳态及其对肥胖的反应的机制： 在目标1中，我们将阐明I型IFN升高驱动eVAT T水平下降的机制， 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 TTRY中的具体作用，以及其扰动如何影响胆固醇稳态。 导致肥胖期间eVAT TdR的失调。 在目标3中，我们将阐明VAT-TdR如何对雌激素信号传导中断的女性肥胖做出反应。 这些努力将支持我们的长期目标，以更好地了解驱动免疫的机制。 与肥胖相关的慢性疾病中的失调。

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.