Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cell Rep. 2020 Dec 29;33(13):108550. doi: 10.1016/j.celrep.2020.108550.
CD4 T cells regulate inflammation and metabolism in obesity. An imbalance of CD4 T regulatory cells (Tregs) is critical in the development of insulin resistance and diabetes. Although cytokine control of this process is well understood, transcriptional regulation is not. KLF10, a member of the Kruppel-like transcription factor family, is an emerging regulator of immune cell function. We generated CD4-T-cell-specific KLF10 knockout (TKO) mice and identified a predisposition to obesity, insulin resistance, and fatty liver due to defects of CD4 Treg mobilization to liver and adipose tissue depots and decreased transforming growth factor β3 (TGF-β3) release in vitro and in vivo. Adoptive transfer of wild-type CD4 Tregs fully rescued obesity, insulin resistance, and fatty liver. Mechanistically, TKO Tregs exhibit reduced mitochondrial respiration and glycolysis, phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR signaling, and consequently impaired chemotactic properties. Collectively, our study identifies CD4 T cell KLF10 as an essential regulator of obesity and insulin resistance by altering Treg metabolism and mobilization.
CD4 T 细胞调节肥胖中的炎症和代谢。CD4 调节性 T 细胞（Tregs）的失衡在胰岛素抵抗和糖尿病的发展中至关重要。尽管细胞因子对这一过程的控制已得到很好的理解，但转录调控却不然。KLF10 是 Kruppel 样转录因子家族的成员，是免疫细胞功能的新兴调节因子。我们生成了 CD4-T 细胞特异性 KLF10 敲除（TKO）小鼠，并发现由于 CD4 Treg 向肝脏和脂肪组织库的动员缺陷以及体外和体内转化生长因子 β3（TGF-β3）释放减少，导致肥胖、胰岛素抵抗和脂肪肝的易感性增加。野生型 CD4 Treg 的过继转移完全挽救了肥胖、胰岛素抵抗和脂肪肝。从机制上讲，TKO Tregs 表现出线粒体呼吸和糖酵解、磷酸肌醇 3-激酶（PI3K）-Akt-mTOR 信号的减少，因此趋化特性受损。总的来说，我们的研究表明，CD4 T 细胞 KLF10 通过改变 Treg 代谢和动员，成为肥胖和胰岛素抵抗的重要调节因子。
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