Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis
Tregs facilitate obesity and insulin resistance via a Blimp-1/IL-10 axis
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Tregs通过Blimp-1/IL-10轴促进肥胖和胰岛素抵抗
DOI：
10.1172/jci.insight.140644
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发表时间：
2021-02-08
期刊：
影响因子：
8
通讯作者：
D'Cruz, Louise M.
中科院分区：
文献类型：
--
作者：
Beppu, Lisa Y.;Mooli, Raja Gopal Reddy;D'Cruz, Louise M.
白细胞介素-10 （IL-10）是免疫细胞用于抑制炎症的关键细胞因子。矛盾的是，免疫细胞来源的IL-10可以通过抑制脂肪细胞的能量消耗和产热来驱动肥胖患者的胰岛素抵抗。然而，抑制脂肪细胞产热所必需的IL-10的来源尚不清楚。我们在此表明CD4(+)Foxp3（+）调节性T细胞（treg）是IL-10的重要来源，treg衍生的IL-10可以抑制脂肪细胞的变化。出乎意料的是，treg特异性IL-10的缺失导致高脂肪饮食喂养的雄性小鼠胰岛素敏感性增加和肥胖减少。在机制上，我们确定treg特异性转录因子Blimp-1的缺失（treg特异性IL-10表达的驱动因子）使treg特异性IL-10缺陷小鼠表型化。Blimp-1在treg中的表达缺失导致ST2（+）、KLRG1（+）、il -10分泌treg减少，尤其是在白色脂肪组织中。通过增加白色脂肪组织褐变，blimp -l缺陷小鼠免于葡萄糖耐受不良、胰岛素抵抗和饮食引起的肥胖。综上所述，我们的数据表明，blimp -1通过Tregs调节IL-10分泌，抑制白色脂肪组织的生长，维持脂肪组织的稳态。
Interleukin-10 (IL-10) is a critical cytokine used by immune cells to suppress inflammation. Paradoxically, immune cell-derived IL-10 can drive insulin resistance in obesity by suppressing adipocyte energy expenditure and thermogenesis. However, the source of IL-10 necessary for the suppression of adipocyte thermogenesis is unknown. We show here that CD4(+)Foxp3(+) regulatory T cells (Tregs) are a substantial source of IL-10 and that Treg-derived IL-10 can suppress adipocyte beiging. Unexpectedly, Treg-specific loss of IL-10 resulted in increased insulin sensitivity and reduced obesity in high-fat diet-fed male mice. Mechanistically, we determined that Treg-specific loss of the transcription factor Blimp-1, a driver of IL-10 expression by Tregs, phenocopied the Treg-specific IL-10-deficient mice. Loss of Blimp-1 expression in Tregs resulted in reduced ST2(+)KLRG1(+), IL-10-secreting Tregs, particularly in the white adipose tissue. Blimp-l-deficient mice were protected from glucose intolerance, insulin resistance, and diet-induced obesity, through increased white adipose tissue browning. Taken together, our data show that Blimp-1-regulated IL-10 secretion by Tregs represses white adipose tissue beiging to maintain adipose tissue homeostasis.