Chen Yang, Liu Lin, Calhoun Ryan, Cheng Lan, Merrick David, Steger David J, Seale Patrick
Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sci Adv. 2025 Jan 3;11(1):eads5963. doi: 10.1126/sciadv.ads5963.
Adipocyte lipolysis controls systemic energy levels and metabolic homeostasis. Lipolysis is regulated by posttranslational modifications of key lipolytic enzymes. However, less is known about the transcriptional mechanisms that regulate lipolysis. Here, we identify interferon regulatory factor-2 binding protein 2 (IRF2BP2) as a transcriptional repressor of adipocyte lipolysis. Deletion of in human adipocytes increases lipolysis without affecting glucose uptake, whereas IRF2BP2 overexpression decreases lipolysis. RNA sequencing, and chromatin immunoprecipitation sequencing analyses show that IRF2BP2 represses lipolysis-related genes, including , which encodes hormone sensitive lipase, the rate-limiting enzyme in lipolysis. Adipocyte-selective deletion of in mice increases expression and free fatty acid levels, resulting in adipose tissue inflammation and glucose intolerance. Together, these findings demonstrate that IRF2BP2 restrains adipocyte lipolysis and opens avenues to target lipolysis for the treatment of metabolic disease.
脂肪细胞脂解作用控制全身能量水平和代谢稳态。脂解作用受关键脂解酶的翻译后修饰调控。然而，关于调控脂解作用的转录机制，人们了解较少。在此，我们确定干扰素调节因子2结合蛋白2（IRF2BP2）为脂肪细胞脂解作用的转录抑制因子。在人类脂肪细胞中缺失IRF2BP2可增加脂解作用而不影响葡萄糖摄取，而IRF2BP2过表达则降低脂解作用。RNA测序和染色质免疫沉淀测序分析表明，IRF2BP2抑制脂解相关基因，包括编码激素敏感性脂肪酶（脂解作用中的限速酶）的LIPE。在小鼠中脂肪细胞选择性缺失IRF2BP2会增加LIPE表达和游离脂肪酸水平，导致脂肪组织炎症和葡萄糖不耐受。总之，这些发现表明IRF2BP2抑制脂肪细胞脂解作用，并为靶向脂解作用治疗代谢性疾病开辟了途径。
