Martínez de Morentin P B, Martinez-Sanchez N, Roa J, Ferno J, Nogueiras R, Tena-Sempere M, Dieguez C, Lopez M
(P.B. Martínez de Morentin) Department of Physiology, School of Medicine-CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela (IDIS), 15782, Spain & CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706, Spain.
Curr Mol Med. 2014 Jan;14(1):3-21. doi: 10.2174/1566524013666131118103706.
Optimal cellular function and therefore organism's survival is determined by the sensitive and accurate convergence of energy and nutrient abundance to cell growth and division. Among other factors, this integration is coupled by the target of rapamycin (TOR) pathway, which is able to sense nutrient, energy and oxygen availability and also growth factor signaling. Indeed, TOR signaling regulates cell energy homeostasis by coordinating anabolic and catabolic processes for survival. TOR, named mTOR in mammals, is a conserved serine/threonine kinase that exists in two different complexes, mTORC1 and mTORC2. Recently, studies are suggesting that alterations of those complexes promote disease and disrupted phenotypes, such as aging, obesity and related disorders and even cancer. The evidences linking mTOR to energy and metabolic homeostasis included the following. At central level mTOR regulates food intake and body weight being involved in the mechanism by which signals such as leptin and ghrelin exert its effects. At peripheral level it influences adipogenesis and lipogenesis in different tissues including the liver. Noteworthy chronic nutritional activation of mTOR signaling has been implicated in the development of beta cell mass expansion and on insulin resistance. Understanding of mTOR and other molecular switches, such as AMP-activated protein kinase (AMPK), as well as their interrelationship is crucial to know how organisms maintain optimal homeostasis. This review summarizes the role of hypothalamic TOR complex in cellular energy sensing, evidenced in the last years, focusing on the metabolic pathways where it is involved and the importance of this metabolic sensor in cellular and whole body energy management. Understanding the exact role of hypothalamic mTOR may provide new cues for therapeutic intervention in diseases.
最佳细胞功能乃至生物体的存活取决于能量和营养物质的充足程度与细胞生长和分裂之间灵敏而精确的协同作用。在诸多因素中，这种整合作用由雷帕霉素靶蛋白（TOR）信号通路介导，该通路能够感知营养物质、能量和氧气的可利用性以及生长因子信号。实际上，TOR信号通过协调合成代谢和分解代谢过程来调节细胞能量稳态，以维持细胞存活。TOR在哺乳动物中被称为mTOR，是一种保守的丝氨酸/苏氨酸激酶，存在于两种不同的复合物中，即mTORC1和mTORC2。最近的研究表明，这些复合物的改变会引发疾病和出现异常表型，如衰老、肥胖及相关疾病，甚至癌症。将mTOR与能量和代谢稳态联系起来的证据如下。在中枢层面，mTOR通过参与瘦素和胃饥饿素等信号发挥作用的机制来调节食物摄入和体重。在周边层面，它会影响包括肝脏在内的不同组织中的脂肪生成和脂质生成。值得注意的是，mTOR信号的慢性营养激活与β细胞量的增加及胰岛素抵抗的发展有关。了解mTOR和其他分子开关，如腺苷酸活化蛋白激酶（AMPK），以及它们之间的相互关系，对于理解生物体如何维持最佳稳态至关重要。本综述总结了近年来所证实的下丘脑TOR复合物在细胞能量感知中的作用，重点关注其涉及的代谢途径以及这种代谢传感器在细胞和全身能量管理中的重要性。了解下丘脑mTOR的确切作用可能为疾病的治疗干预提供新线索。
