Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
Diabetes. 2017 May;66(5):1146-1158. doi: 10.2337/db16-1546. Epub 2017 Feb 17.
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.
尽管已经确定了激活转录因子 4（ATF4）的许多生物学功能，但下丘脑 ATF4 在调节能量平衡中的作用还知之甚少。在这项研究中，我们表明下丘脑促黑皮质素原（POMC）神经元特异性 ATF4 敲除（PAKO）小鼠体型偏瘦，能量消耗更高。此外，PAKO 小鼠对高脂肪饮食诱导的肥胖、葡萄糖不耐受和瘦素抵抗具有抗性。此外，ATF4 的敲低或过表达分别增加或减少自噬蛋白 5（ATG5）的表达，并且 ATF4 通过与启动子上的基本拉链蛋白结合位点抑制 ATG5 的转录。重要的是，与 PAKO 小鼠相比，在高脂肪饮食下，POMC 神经元中 ATF4 和 ATG5 双敲除的小鼠获得了更多的脂肪量并减少了能量消耗。最后，POMC 神经元中 ATF4 缺失的作用可能是通过增强下丘脑 ATG5 依赖性自噬和α-促黑素细胞激素的产生介导的。总之，这些结果表明下丘脑 ATF4/ATG5 轴在调节能量消耗、肥胖和肥胖相关代谢紊乱方面具有有益作用，这表明下丘脑 ATF4/ATG5 轴可能是治疗肥胖和肥胖相关代谢疾病的新潜在治疗靶点。
