Feedback regulation of Arid5a and Ppar-γ2 maintains adipose tissue homeostasis
Feedback regulation of Arid5a and Ppar-γ2 maintains adipose tissue homeostasis
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DOI：
10.1073/pnas.1906712116
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发表时间：
2019-07-23
影响因子：
11.1
通讯作者：
Kishimoto, Tadamitsu
中科院分区：
文献类型：
--
作者：
Chalise, Jaya Prakash;Hashimoto, Shigeru;Kishimoto, Tadamitsu
免疫细胞浸润脂肪组织，并提供一个框架，以调节能量稳态。然而，免疫系统调节代谢组织中能量稳态的确切潜在机制和信号传导仍然知之甚少。在这里，我们表明，AT丰富的相互作用域5A（Arid 5a），一个精氨酸诱导的核酸结合蛋白，是重要的脂肪组织的稳态维持。Arid 5a在小鼠中的长期缺乏导致成年发作的严重肥胖。相反，过表达Arid 5a的转基因小鼠对高脂饮食诱导的肥胖具有高度抵抗力。Arid 5a的抑制促进3 T3-L1细胞和成纤维细胞向脂肪细胞的体外分化，而其诱导实质上抑制它们的分化。分子研究表明，Arid 5a抑制过氧化物酶体增殖物激活受体γ 2（Ppar-gamma 2）的转录，因此，在Arid 5a不存在的情况下，Ppar-gamma 2在成纤维细胞中持续表达。这种现象伴随着Arid 5a缺陷细胞中脂肪酸摄取的增强，这使代谢稳态向前脂代谢转变。此外，我们表明，Arid 5a和Ppar-gamma 2动态相互反调节，从而维持脂肪形成的稳态。因此，我们表明Arid 5a是能量代谢的重要负调节因子，可以成为代谢紊乱的潜在靶点。
Immune cells infiltrate adipose tissues and provide a framework to regulate energy homeostasis. However, the precise underlying mechanisms and signaling by which the immune system regulates energy homeostasis in metabolic tissues remain poorly understood. Here, we show that the AT-rich interactive domain 5A (Arid5a), a cytokine-induced nucleic acid binding protein, is important for the maintenance of adipose tissue homeostasis. Long-term deficiency of Arid5a in mice results in adult-onset severe obesity. In contrast, transgenic mice overexpressing Arid5a are highly resistant to high-fat diet-induced obesity. Inhibition of Arid5a facilitates the in vitro differentiation of 3T3-L1 cells and fibroblasts to adipocytes, whereas its induction substantially inhibits their differentiation. Molecular studies reveal that Arid5a represses the transcription of peroxisome proliferator activated receptor gamma 2 (Ppar-gamma 2) due to which, in the absence of Arid5a, Ppar-gamma 2 is persistently expressed in fibroblasts. This phenomenon is accompanied by enhanced fatty acid uptake in Arid5a-deficient cells, which shifts metabolic homeostasis toward prolipid metabolism. Furthermore, we show that Arid5a and Ppar-gamma 2 are dynamically counterregulated by each other, hence maintaining adipogenic homeostasis. Thus, we show that Arid5a is an important negative regulator of energy metabolism and can be a potential target for metabolic disorders.