Diabetes：郭非凡等揭示亮氨酸缺乏时中枢神经系统调节外周能量代谢的新机制

近日，国际学术期刊Diabetes在线发表了上海生科院营养所郭非凡研究组的研究论文 “ S6K1 in the CNS regulates energy expenditure via MC4R/CRH pathways in response to deprivation of an essential amino acid ”。该研究首次发现下丘脑核糖体S6K蛋白激酶 (p70 S6K1)通过抑制黑素皮质素受体4（MC4R）的表达进而下调促肾上腺皮质激素释放激素(corticotropin-releasing hormone, CRH)水平，参与机体能量代谢稳态调控，揭示了亮氨酸缺乏时中枢神经系统调节外周脂质和能量代谢的新机制。

中枢神经系统的营养感应信号通路与外周组织的代谢分子调控网络关系密切，其功能紊乱是促发代谢性疾病的重要原因。中枢神经系统，特别是下丘脑，在营养素感应和调控代谢过程中扮演重要角色。下丘脑兼有神经和内分泌系统的双重功能，能够直接感受机体的营养状态，通过营养感应信号通路激活对外周组织的代谢调控。该研究组前期研究发现了中枢注射亮氨酸能够改变白色脂肪组织激素敏感脂肪酶(hormone-sensitive lipase, HSL)的磷酸化水平和褐色脂肪组织解耦联蛋白1 (uncoupling protein 1, UCP1)的表达水平；并且亮氨酸缺乏导致下丘脑中室旁核中CRH表达增加，进而激活交感神经系统，促进外周脂质和能量代谢。但是，亮氨酸缺乏如何激活CRH进而调节外周能量代谢的分子机制尚不清楚。

在本研究中，郭非凡研究组的博士生夏婷婷等人研究发现，亮氨酸缺乏引起小鼠下丘脑中核糖体S6K1蛋白激酶活性显著下降；而第三脑室注射腺病毒介导的持续激活S6K1（CA-S6K1）能有效阻断亮氨酸缺乏引起的下丘脑室旁核中CRH表达增加、褐色脂肪组织UCP1 表达增加以及机体能量消耗的增加；进一步研究证实脑室注射CRH激素能够逆转S6K1持续激活对亮氨酸缺乏导致代谢变化的影响；从而证实亮氨酸缺乏引起下丘脑S6K1表达下调，进而激活下丘脑室旁核中CRH表达，促进了外周脂质和能量代谢；通过下丘脑原代细胞培养实验进一步揭示了S6K1对CRH的表达调控依赖于MC4R。

该项研究首次证明了下丘脑CRH的表达受S6K1调控，而S6K1是亮氨酸缺乏引起能量代谢变化的核心调节因子。该研究成果为进一步研究中枢感应氨基酸及调控外周能量代谢奠定了基础，丰富了人们对中枢神经系统调控外周代谢的认识，有助于加深人们对肥胖及相关过代谢性疾病发生机制的理解。

该项工作得到科技部973计划、自然科学基金委、上海市科委以及中科院等科研基金的支持。

doi:10.2337/db11-1278
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S6K1 in the Central Nervous System Regulates Energy Expenditure via MC4R/Corticotropin-Releasing Hormone Pathways in Response to Deprivation of an Essential Amino Acid

Tingting Xia, Ying Cheng, Qian Zhang, Fei Xiao, Bin Liu, Shanghai Chen and Feifan Guo⇓

It is well established that the central nervous system (CNS), especially the hypothalamus, plays an important role in regulating energy homeostasis and lipid metabolism. We have previously shown that hypothalamic corticotropin-releasing hormone (CRH) is critical for stimulating fat loss in response to dietary leucine deprivation. The molecular mechanisms underlying the CNS regulation of leucine deprivation–stimulated fat loss are, however, still largely unknown. Here, we used intracerebroventricular injection of adenoviral vectors to identify a novel role for hypothalamic p70 S6 kinase 1 (S6K1), a major downstream effector of the kinase mammalian target of rapamycin, in leucine deprivation stimulation of energy expenditure. Furthermore, we show that the effect of hypothalamic S6K1 is mediated by modulation of Crh expression in a melanocortin-4 receptor–dependent manner. Taken together, our studies provide a new perspective for understanding the regulation of energy expenditure by the CNS and the importance of cross-talk between nutritional control and regulation of endocrine signals.