ATF4/ATG5 Signaling in Hypothalamic Proopiomelanocortin Neurons Regulates Fat Mass via Affecting Energy Expenditure
ATF4/ATG5 Signaling in Hypothalamic Proopiomelanocortin Neurons Regulates Fat Mass via Affecting Energy Expenditure
复制标题
下丘脑阿黑皮质素原神经元中的 ATF4/ATG5 信号通过影响能量消耗来调节脂肪量
作者：
Xiao Yuzhong;Deng Yalan;Yuan Feixiang;Xia Tingting;Liu Hao;Li Zhigang;Liu Zhixue;Ying Hao;Liu Yi;Zhai Qiwei;Chen Shanghai;Guo Feifan
虽然许多生物学功能的激活转录因子4（ATF 4）已被确定，下丘脑ATF 4的能量稳态的调节作用知之甚少。在这项研究中，我们发现下丘脑前阿黑皮素（POMC）神经元特异性ATF 4敲除（PAKO）小鼠是瘦的，具有较高的能量消耗。此外，PAKO小鼠对高脂饮食诱导的肥胖、葡萄糖耐受不良和瘦素抵抗具有抗性。此外，自噬蛋白5（ATG 5）的表达增加或减少，分别通过ATF 4敲低或过表达，和ATF 4抑制ATG 5的转录通过结合到其启动子上的碱性拉链蛋白位点。重要的是，与高脂饮食下的PAKO小鼠相比，POMC神经元中ATF 4和ATG 5双敲除的小鼠获得了更多的脂肪量和减少的能量消耗。最后，POMC神经元中ATF 4缺失的作用可能通过增强下丘脑中ATG 5依赖的自噬和α-黑素细胞刺激激素的产生来介导。综上所述，这些结果确定了下丘脑ATF 4/ATG 5轴在调节能量消耗、肥胖和肥胖相关代谢紊乱中的有益作用，这表明下丘脑中的ATF 4/ATG 5轴可能是治疗肥胖和肥胖相关代谢疾病的新的潜在治疗靶点。
Although many biological functions of activating transcription factor 4 (ATF4) have been identified, a role of hypothalamic ATF4 in the regulation of energy homeostasis is poorly understood. In this study, we showed that hypothalamic proopiomelanocortin (POMC) neuron–specific ATF4 knockout (PAKO) mice are lean and have higher energy expenditure. Furthermore, PAKO mice were resistant to high-fat diet–induced obesity, glucose intolerance, and leptin resistance. Moreover, the expression of autophagy protein 5 (ATG5) was increased or decreased by ATF4 knockdown or overexpression, respectively, and ATF4 inhibited the transcription of ATG5 by binding to the basic zipper-containing protein sites on its promoter. Importantly, mice with double knockout of ATF4 and ATG5 in POMC neurons gained more fat mass and reduced energy expenditure compared with PAKO mice under a high-fat diet. Finally, the effect of ATF4 deletion in POMC neurons was possibly mediated via enhanced ATG5-dependent autophagy and α-melanocyte–stimulating hormone production in the hypothalamus. Taken together, these results identify the beneficial role of hypothalamic ATF4/ATG5 axis in the regulation of energy expenditure, obesity, and obesity-related metabolic disorders, which suggests that ATF4/ATG5 axis in the hypothalamus may be a new potential therapeutic target for treating obesity and obesity-related metabolic diseases.