Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell. 2018 Jan 11;172(1-2):218-233.e17. doi: 10.1016/j.cell.2017.11.019. Epub 2017 Dec 14.
Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase-accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPβ recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy.
促进脂肪组织产热的信号通路已经得到很好的描述，但能量消耗的限制因素在很大程度上尚不清楚。在这里，我们表明，抗炎细胞因子 IL-10 的缺失可改善胰岛素敏感性，防止饮食诱导的肥胖，并引发白色脂肪组织的褐色化。机制研究将骨髓细胞定义为 IL-10 信号的来源，脂肪细胞是介导这些作用的靶细胞类型。IL-10 受体 α 在成熟脂肪细胞中高度富集，并在分化、肥胖和衰老时被诱导。转座酶可及染色质测序 (ATAC-seq)、ChIP-seq 和 RNA-seq 分析表明，IL-10 通过改变染色质可及性并抑制 ATF 和 C/EBPβ 募集到关键增强子区域，从而抑制脂肪细胞中产热基因的转录。这些发现扩展了我们对炎症信号通路与脂肪组织功能之间关系的理解，并为产热的生理控制提供了新的见解，这可能为未来的治疗提供信息。
