The KRAB Domain-Containing Protein ZFP961 Represses Adipose Thermogenesis and Energy Expenditure through Interaction with PPARα.
The KRAB Domain-Containing Protein ZFP961 Represses Adipose Thermogenesis and Energy Expenditure through Interaction with PPARα.
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DOI：
10.1002/advs.202102949
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Wang YX
中科院分区：
文献类型：
--
作者：
Huang L;Liu P;Yang Q;Wang YX
脂肪产热在全身代谢稳态中起着关键作用。虽然促进产热的转录机制被广泛研究，但负调控网络仍然知之甚少。在这里，一个Krüppel相关框（KRAB）结构域的锌指蛋白，ZFP 961，作为一个有效的阻遏物的产热程序被确定。ZFP 961表达由脂肪组织中的冷和β3-肾上腺素能激动剂诱导。ZFP 961抑制棕色脂肪选择性基因表达和线粒体呼吸，对培养的脂肪细胞中的一般脂肪形成没有任何影响。ZFP 961的脂肪特异性敲低和过表达产生显著和相反的白色脂肪重塑表型。ZFP 961敲除小鼠显示出强烈的腹股沟白色脂肪组织布朗宁，其通过全长ZFP 961的再表达而消除，但不通过KRAB结构域缺失的ZFP 961突变体消除。ZFP 961缺陷型小鼠具有耐寒性，并对高脂饮食诱导的肥胖、高血糖症和肝脂肪变性具有抗性。ZFP 961通过直接与PPARα相互作用并阻断其转录活性来抑制产热基因的表达，这可以被PPARα激动剂完全否定。这些发现揭示了ZFP 961是一种关键的生理制动器，可以限制脂肪产热，并为维持能量平衡和组织稳态的调节机制提供了见解。这项研究为维持全身能量平衡和组织稳态的负反馈机制提供了新的见解。含有Krüppel相关盒结构域的锌指蛋白ZFP 961是保护脂肪产热的关键生理制动器。ZFP 961与PPARα相互作用，抑制产热基因表达，防止能量过度消耗。
Adipose thermogenesis plays a pivotal role in whole‐body metabolic homeostasis. Although transcriptional mechanisms that promote thermogenesis are extensively studied, the negative regulatory network is still poorly understood. Here, a Krüppel‐associated box (KRAB) domain‐containing zinc finger protein, ZFP961, as a potent repressor of the thermogenic program is identified. ZFP961 expression is induced by cold and β3‐adrenergic agonist in adipose tissue. ZFP961 represses brown fat‐selective gene expression and mitochondrial respiration without any effect on general adipogenesis in cultured adipocytes. Adipose‐specific knockdown and overexpression of ZFP961 produce remarkable and opposite phenotypes of white fat remodeling. ZFP961 knockout mice display robust inguinal white adipose tissue browning, which is abolished by reexpression of full‐length ZFP961, but not by KRAB domain‐deleted ZFP961 mutant. ZFP961‐deficient mice are cold tolerant and resistant to high‐fat diet‐induced obesity, hyperglycemia, and hepatic steatosis. ZFP961 suppresses thermogenic gene expression by directly interacting with PPARα and blocking its transcriptional activity, which can be completely negated by the PPARα agonist. The findings uncover ZFP961 as a critical physiological brake that limits adipose thermogenesis and provides insights into the regulatory mechanisms that maintain energy balance and tissue homeostasis. This study provides new insights into the negative feedback mechanisms that sustain whole‐body energy balance and tissue homeostasis. Krüppel‐associated box domain‐containing zinc finger protein ZFP961 serves as a critical physiological brake to safeguard adipose thermogenesis. ZFP961 interacts with PPARα to repress thermogenic gene expression and prevent energy over‐consumption.
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