Enhancement of Hypothalamic STAT3 Acetylation by Nuclear Receptor Nur77 Dictates Leptin Sensitivity
Enhancement of Hypothalamic STAT3 Acetylation by Nuclear Receptor Nur77 Dictates Leptin Sensitivity
复制标题
核受体 Nur77 增强下丘脑 STAT3 乙酰化决定瘦素敏感性
DOI：
10.2337/db14-1206
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发表时间：
2015-06-01
期刊：
影响因子：
7.7
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
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作者：
Chen, Yan;Wu, Rong;Wu, Qiao
瘦素是下丘脑中的一种促肾上腺皮质激素，抑制食物摄入并增加能量消耗。对瘦素没有反应会导致肥胖。在这里，我们发现核受体Nur77的表达是较低的肥胖小鼠下丘脑与正常小鼠相比。注射瘦素导致野生型小鼠体重显著降低，但在Nur77敲除（KO）同窝小鼠或下丘脑特异性Nur77敲除的小鼠中没有。下丘脑Nur77不仅参与瘦素对食物摄入的中枢控制，而且还将瘦素的作用范围扩大到肝脏和脂肪组织，以调节脂质代谢。Nur77通过募集乙酰化酶p300和去乙酰化酶组蛋白去乙酰化酶1（HDAC 1）促进信号转导和转录激活因子3（STAT 3）乙酰化，从而增强STAT 3的转录活性，并因此调节下游基因Pomc在下丘脑中的表达。Nur77缺乏会影响高脂饮食小鼠对瘦素的反应Nur77 KO小鼠中的严重瘦素抵抗伴随食欲增加、能量消耗降低和高瘦素血症，导致衰老诱导的肥胖。我们的研究开辟了一个新的途径，调节代谢与Nur77作为积极的调节剂在瘦素驱动的减肥在下丘脑。
Leptin, an anorexigenic hormone in the hypothalamus, suppresses food intake and increases energy expenditure. Failure to respond to leptin will lead to obesity. Here, we discovered that nuclear receptor Nur77 expression is lower in the hypothalamus of obese mice compared with normal mice. Injection of leptin results in significant reduction in body weight in wild-type mice but not in Nur77 knockout (KO) littermates or mice with specific Nur77 knockdown in the hypothalamus. Hypothalamic Nur77 not only participates in leptin central control of food intake but also expands leptin’s reach to liver and adipose tissues to regulate lipid metabolism. Nur77 facilitates signal transducer and activator of transcription 3 (STAT3) acetylation by recruiting acetylase p300 and disassociating deacetylase histone deacetylase 1 (HDAC1) to enhance the transcriptional activity of STAT3 and consequently modulates the expression of downstream gene Pomc in the hypothalamus. Nur77 deficiency compromises response to leptin in mice fed a high-fat diet. Severe leptin resistance in Nur77 KO mice with increased appetite, lower energy expenditure, and hyperleptinemia contributes to aging-induced obesity. Our study opens a new avenue for regulating metabolism with Nur77 as the positive modulator in the leptin-driven antiobesity in the hypothalamus.