Department of Immunology, Harvard Medical School, Boston, MA, USA.
Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
Immunity. 2024 Jun 11;57(6):1345-1359.e5. doi: 10.1016/j.immuni.2024.04.002. Epub 2024 Apr 30.
Regulatory T (Treg) cells in epidydimal visceral adipose tissue (eVAT) of lean mice and humans regulate metabolic homeostasis. We found that constitutive or punctual depletion of eVAT-Treg cells reined in the differentiation of stromal adipocyte precursors. Co-culture of these precursors with conditional medium from eVAT-Treg cells limited their differentiation in vitro, suggesting a direct effect. Transcriptional comparison of adipocyte precursors, matured in the presence or absence of the eVAT-Treg-conditioned medium, identified the oncostatin-M (OSM) signaling pathway as a key distinction. Addition of OSM to in vitro cultures blocked the differentiation of adipocyte precursors, while co-addition of anti-OSM antibodies reversed the ability of the eVAT-Treg-conditioned medium to inhibit in vitro adipogenesis. Genetic depletion of OSM (specifically in Treg) cells or of the OSM receptor (specifically on stromal cells) strongly impaired insulin sensitivity and related metabolic indices. Thus, Treg-cell-mediated control of local progenitor cells maintains adipose tissue and metabolic homeostasis, a regulatory axis seemingly conserved in humans.
附睾内脏脂肪组织（eVAT）中的调节性 T（Treg）细胞在瘦鼠和人类中调节代谢稳态。我们发现，eVAT-Treg 细胞的组成性或点状耗竭抑制了基质脂肪细胞前体的分化。将这些前体与来自 eVAT-Treg 细胞的条件培养基共培养，限制了它们在体外的分化，表明存在直接作用。对存在或不存在 eVAT-Treg 条件培养基的脂肪细胞前体进行转录比较，确定了肿瘤坏死因子-α（OSM）信号通路为关键区别。向体外培养物中添加 OSM 阻断了脂肪细胞前体的分化，而共添加抗 OSM 抗体则逆转了 eVAT-Treg 条件培养基抑制体外脂肪生成的能力。OSM（特异性在 Treg 细胞中）或 OSM 受体（特异性在基质细胞上）的基因耗竭强烈损害了胰岛素敏感性和相关代谢指标。因此，Treg 细胞介导的局部祖细胞控制维持脂肪组织和代谢稳态，这一调节轴在人类中似乎是保守的。
