An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity
An ATF4-ATG5 signaling in hypothalamic POMC neurons regulates obesity
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下丘脑 POMC 神经元中的 ATF4-ATG5 信号传导调节肥胖
DOI：
10.1080/15548627.2017.1307488
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发表时间：
2017
期刊：
影响因子：
13.3
通讯作者：
Guo Feifan
中科院分区：
文献类型：
--
作者：
Xiao Yuzhong;Deng Yalan;Yuan Feixiang;Xia Tingting;Liu Hao;Li Zhigang;Chen Shanghai;Liu Zhixue;Ying Hao;Liu Yi;Zhai Qiwei;Guo Feifan
ATF 4（activating transcription factor 4）是一种重要的转录因子，具有多种生物学功能，但其在下丘脑POMC（pro-opiomelanocortin-α）神经元能量稳态调节中的作用尚不清楚。我们最近发现，POMC神经元特异性Atf 4缺失的小鼠（PAKO小鼠）更瘦，能量消耗更高。此外，这些小鼠对高脂饮食（HFD）诱导的肥胖和肥胖相关的代谢紊乱具有抗性。从机制上讲，我们发现ATG 5（自噬相关5）的表达在PAKO小鼠的POMC神经元中上调，ATF 4通过直接结合其启动子来调节ATG 5的表达。POMC神经元Atf 4和Atg 5双敲除小鼠与HFD下的PAKO小鼠相比，能量消耗减少，脂肪量增加。最后，Atf 4基因敲除对POMC神经元的影响可能是通过增强下丘脑中ATG 5依赖的巨自噬/自噬和α-黑素细胞刺激激素（α-MSH）的产生来介导的。总之，这项工作不仅确定了下丘脑POMC神经元中ATF 4在肥胖调节中的有益作用，而且还为肥胖和肥胖相关代谢疾病提供了新的潜在治疗靶点。
ATF4 (activating transcription factor 4) is an important transcription factor that has many biological functions, while its role in hypothalamic POMC (pro-opiomelanocortin-α) neurons in the regulation of energy homeostasis has not been explored. We recently discovered that mice with anAtf4deletion specific to POMC neurons (PAKO mice) are lean and have higher energy expenditure. Furthermore, these mice are resistant to high-fat diet (HFD)-induced obesity and obesity-related metabolic disorders. Mechanistically, we found the expression of ATG5 (autophagy-related 5) is upregulated in POMC neurons of PAKO mice, and ATF4 regulates ATG5 expression by binding directly to its promoter. Mice withAtf4andAtg5double knockout in POMC neurons have reduced energy expenditure and gain more fat mass compared with PAKO mice under a HFD. Finally, the effect ofAtf4knockout in POMC neurons is possibly mediated by enhanced ATG5-dependent macroautophagy/autophagy and α-melanocyte-stimulating hormone (α-MSH) production in the hypothalamus. Together, this work not only identifies a beneficial role for ATF4 in hypothalamic POMC neurons in the regulation of obesity, but also provides a new potential therapeutic target for obesity and obesity-related metabolic diseases.