Brd4 modulates diet-induced obesity via PPAR.-dependent Gdf3 expression in adipose tissue macrophages
Brd4 modulates diet-induced obesity via PPAR.-dependent Gdf3 expression in adipose tissue macrophages
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Brd4 通过脂肪组织巨噬细胞中 PPARγ 依赖性 Gdf3 表达调节饮食诱导的肥胖
DOI：
10.1172/jci.insight.143379
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发表时间：
2021-04-08
期刊：
影响因子：
8
通讯作者：
Chen, Lin-Feng
中科院分区：
文献类型：
--
作者：
Hu, Xiangming;Dong, Xingchen;Chen, Lin-Feng
巨噬细胞介导的炎症反应参与了肥胖和胰岛素抵抗的发病机制。BRD4已成为先天免疫反应的关键调节因子。然而，Brd4在肥胖相关炎症和胰岛素抵抗中的作用仍不明确。在这里，我们证明了髓系特异性Brd4基因敲除(Brd4-CKO)小鼠在高脂饮食诱导的(HFD诱导)肥胖中受到保护，脂肪积累较少，能量消耗较高，脂肪组织中的脂肪分解增加。喂食HFD的BRD4-CKO小鼠也表现出局部和全身炎症减轻，胰岛素敏感性提高。用HFD喂养的WT和Brd4-CKO小鼠脂肪组织巨噬细胞(ATM)的RNA-SEQ结果显示，Brd4-CKO小鼠脂肪组织巨噬细胞中抗脂因子GDF3的表达显著降低。我们还发现Brd4与GDF3的启动子和增强子结合，以促进巨噬细胞中依赖于PPARγ的GDF3的表达。此外，Brd4介导的GDF3的表达作为针对脂肪细胞的旁分泌信号，抑制培养细胞和小鼠中脂肪酶的表达和相关的脂解。控制ATM中GDF3的表达可能是Brd4调节脂代谢和饮食诱导肥胖的机制之一。这项研究表明，Brd4可能是治疗肥胖和胰岛素抵抗的潜在靶点。
Macrophage-mediated inflammatory response has been implicated in the pathogenesis of obesity and insulin resistance. Brd4 has emerged as a key regulator in the innate immune response. However, the role of Brd4 in obesity-associated inflammation and insulin resistance remains uncharacterized. Here, we demonstrated that myeloid lineage-specific Brd4 knockout (Brd4-CKO) mice were protected from high-fat diet–induced (HFD-induced) obesity with less fat accumulation, higher energy expenditure, and increased lipolysis in adipose tissue. Brd4-CKO mice fed a HFD also displayed reduced local and systemic inflammation with improved insulin sensitivity. RNA-Seq of adipose tissue macrophages (ATMs) from HFD-fed WT and Brd4-CKO mice revealed that expression of antilipolytic factor Gdf3 was significantly decreased in ATMs of Brd4-CKO mice. We also found that Brd4 bound to the promoter and enhancers of Gdf3 to facilitate PPARγ-dependent Gdf3 expression in macrophages. Furthermore, Brd4-mediated expression of Gdf3 acted as a paracrine signal targeting adipocytes to suppress the expression of lipases and the associated lipolysis in cultured cells and mice. Controlling the expression of Gdf3 in ATMs could be one of the mechanisms by which Brd4 modulates lipid metabolism and diet-induced obesity. This study suggests that Brd4 could be a potential therapeutic target for obesity and insulin resistance.