Kissig Megan, Ishibashi Jeff, Harms Matthew J, Lim Hee-Woong, Stine Rachel R, Won Kyoung-Jae, Seale Patrick
Institute for Diabetes, Obesity & Metabolism, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Cell and Developmental Biology, Smilow Center for Translational Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
EMBO J. 2017 Jun 1;36(11):1528-1542. doi: 10.15252/embj.201695588. Epub 2017 Apr 13.
Brown adipose has the potential to counteract obesity, and thus, identifying signaling pathways that regulate the activity of this tissue is of great clinical interest. PRDM16 is a transcription factor that activates brown fat-specific genes while repressing white fat and muscle-specific genes in adipocytes. Whether PRDM16 also controls other gene programs to regulate adipocyte function was unclear. Here, we identify a novel role for PRDM16 in suppressing type I interferon (IFN)-stimulated genes (ISGs), including , in adipocytes and Ectopic activation of type I IFN signaling in brown adipocytes induces mitochondrial dysfunction and reduces uncoupling protein 1 (UCP1) expression. -deficient adipose displays an exaggerated response to type I IFN, including higher STAT1 levels and reduced mitochondrial gene expression. Mechanistically, PRDM16 represses ISGs through binding to promoter regions of these genes and blocking the activating function of IFN regulatory factor 1 (IRF1). Together, these data indicate that PRDM16 diminishes responsiveness to type I IFN in adipose cells to promote thermogenic and mitochondrial function.
棕色脂肪具有对抗肥胖的潜力，因此，确定调节该组织活性的信号通路具有重大临床意义。PRDM16是一种转录因子，可激活棕色脂肪特异性基因，同时抑制脂肪细胞中的白色脂肪和肌肉特异性基因。PRDM16是否还控制其他基因程序以调节脂肪细胞功能尚不清楚。在这里，我们确定了PRDM16在抑制I型干扰素（IFN）刺激基因（ISGs）方面的新作用，包括在脂肪细胞中，棕色脂肪细胞中I型IFN信号的异位激活会诱导线粒体功能障碍并降低解偶联蛋白1（UCP1）的表达。缺乏该基因的脂肪对I型IFN表现出过度反应，包括更高的STAT1水平和降低的线粒体基因表达。从机制上讲，PRDM16通过与这些基因的启动子区域结合并阻断IFN调节因子1（IRF1）的激活功能来抑制ISGs。总之，这些数据表明PRDM16降低了脂肪细胞对I型IFN的反应性，以促进产热和线粒体功能。
