The visceral adipose tissue (VAT) of lean mice hosts a unique population of regulatory T cells (Tregs) that have a distinct transcriptome and T cell receptor (TCR) repertoire and regulate local and systemic inflammation and metabolism. Perplexingly, this population disappears in obese mice, limiting the promise of Treg-based therapies for metabolic disorders. We exploited the power of a VAT-Treg TCR-transgenic mouse model to follow the dynamics of, and phenotypic changes in, the VAT-Treg population throughout the development of diet-induced obesity. Our results show that VAT-Tregs are lost under obesogenic conditions due to downregulation of their defining transcription factor, PPARγ, coupled with their strikingly enhanced responses to pro-inflammatory cytokines. In particular, the VAT from obese mice (and reportedly humans) was strongly enriched in plasmacytoid dendritic cells that actively express interferon-alpha. These cells were directly toxic to PPARγ⁺ VAT-Tregs. Blocking this pathway in obese mice by multiple approaches substantially restored the VAT-Treg population and enhanced insulin sensitivity.

瘦小鼠的内脏脂肪组织 (VAT) 拥有一组独特的调节性 T 细胞 (Tregs)，它们具有独特的转录组和 T 细胞受体 (TCR) 库并调节局部和全身炎症和代谢。令人费解的是，这一群体在肥胖小鼠中消失了，限制了基于 Treg 的代谢紊乱疗法的前景。我们利用 VAT-Treg TCR 转基因小鼠模型的力量来跟踪 VAT-Treg 种群在整个饮食诱导肥胖发展过程中的动态和表型变化。我们的研究结果表明，VAT-Tregs 在肥胖条件下丢失，这是由于其定义的转录因子 PPARγ 的下调，以及它们对促炎细胞因子的显着增强反应。尤其是，来自肥胖小鼠（据报道是人类）的 VAT 富含浆细胞样树突状细胞，这些树突状细胞积极表达干扰素-α。这些细胞对 PPARγ 有直接毒性⁺ VAT-Tregs。通过多种方法阻断肥胖小鼠体内的这一通路可显着恢复 VAT-Treg 群体并增强胰岛素敏感性。