Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that...Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.展开更多
色氨酸作为机体必需氨基酸,参与蛋白质合成,还通过5-羟色胺和犬尿氨酸代谢途径产生重要的活性化合物,诱导激活细胞内多种信号通路,在细胞生长、增殖以及代谢平衡等过程中发挥重要作用,且呈剂量依赖性。色氨酸可通过激活哺乳动物雷帕霉...色氨酸作为机体必需氨基酸,参与蛋白质合成,还通过5-羟色胺和犬尿氨酸代谢途径产生重要的活性化合物,诱导激活细胞内多种信号通路,在细胞生长、增殖以及代谢平衡等过程中发挥重要作用,且呈剂量依赖性。色氨酸可通过激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、酪氨酸蛋白激酶2/信号转导与转录激活因子3(Janus kinase 2/signal transducer and activator of transcription 3,JAK2/STAT3)信号通路和一般性调控阻遏蛋白激酶2(general control non-derepressible 2,GCN2)经典应激反应促进细胞增殖;5-羟色胺经其受体(5-hydroxytryptamine receptor,5-HTR)和转运体(serotonin transporter,SETR)内化后激活下游信号分子,促进细胞增殖。然而高表达的吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)大量消耗色氨酸,导致色氨酸耗竭和代谢物大量累积,从而抑制细胞增殖;同时犬尿氨酸激活芳烃受体(aryl hydrocarbon receptor,AhR),阻滞细胞周期进程,抑制细胞增殖。该文综述了色氨酸代谢途径及其代谢物诱导的多种信号通路对细胞增殖的调控机理,旨在临床靶向治疗时,可通过精准地调控色氨酸代谢的限速酶来治疗由细胞异常增殖而引起的代谢性疾病。展开更多
氨基酸是人必需的营养物质,具有广泛的生物学功能,它是蛋白质的组成单位,能量代谢物质。此外,它还作为信号分子广泛参与对多种生理功能的维持与调控,并在转录、翻译、翻译后修饰等多个层面上发挥作用。肝脏是关键的代谢器官,它充当连接...氨基酸是人必需的营养物质,具有广泛的生物学功能,它是蛋白质的组成单位,能量代谢物质。此外,它还作为信号分子广泛参与对多种生理功能的维持与调控,并在转录、翻译、翻译后修饰等多个层面上发挥作用。肝脏是关键的代谢器官,它充当连接各种组织代谢的枢纽。氨基酸感应在肝脏糖脂代谢的调控中起到十分重要的作用。因此准确地感应细胞内和细胞外氨基酸的水平,成为维持细胞内稳态的关键。真核细胞中存在一些众所周知的氨基酸感应因子,即一般性调控阻遏蛋白激酶2 (general control non-derepressible-2, GCN2)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)以及味觉受体等,在维持机体代谢稳态中发挥重要作用。本文对氨基酸调控肝脏糖脂代谢的作用与机制做了详细介绍,为进一步探究氨基酸感应机制以及治疗肝脏糖脂代谢紊乱疾病奠定了基础。展开更多
From the conventional knowledge of protein nutrition to the molecular nutrition of amino acids, our understanding of protein/amino acid nutrition is rapidly increasing. Amino acids control cell growth and metabolism t...From the conventional knowledge of protein nutrition to the molecular nutrition of amino acids, our understanding of protein/amino acid nutrition is rapidly increasing. Amino acids control cell growth and metabolism through two amino acid-sensingpathways, i.e. target of rapamycin complex 1 (TORC1) and the general control nonderepressible 2 (GCN2) signaling pathway.In the amino acid-abundant status, TORC1 dominates intracellular signaling and increases protein synthesis and cell growth.In contrast, amino acid deprivation actives GCN2 resulting in repression of general protein synthesis but facilitates the aminoacid transport and synthesis process. By integrating and coordinating nutrition and hormone signaling, TORC1 and GCN2control the switch of the catabolism and anabolism phase in most eukaryotes. Now, we appreciate that the availability ofindividual amino acids is sensed by intracellular sensors. These cutting-edge findings expand our knowledge of amino acidnutrition. Although the TORC1 and GCN2 were discovered decades ago, the study of molecular amino acid nutrition inaquaculture animals is still at its infancy. The aquaculture industry is highly dependent on the supply of fishmeal, which isthe major protein source in aquacultural animal diets. Some concerted efforts were conducted to substitute for fishmeal dueto limited supply of it. However, the concomitant issues including the unbalanced amino acid profile of alternative proteinsources limited the utilization of those proteins. Continued study of the molecular nutrition of amino acid in aquacultureanimals may be expected in the immediate future to expand our knowledge on the utilization of alternative protein sources.展开更多
This article provides a brief overview describing how two key signaling pathways, namely the integrated stress response and the mammalian target of rapamycin complex 1, work together to facilitate cellular adaptation ...This article provides a brief overview describing how two key signaling pathways, namely the integrated stress response and the mammalian target of rapamycin complex 1, work together to facilitate cellular adaptation to dietary amino acid insufficiency. A deeper understanding of these mechanisms is leading to identification of novel targets which aid in disease treatments, improve stress recovery and increase health span through slowed aging and enhanced metabolic fitness.展开更多
基金This work was supported by the National Natural Science Foundation of China(31830044,91957207,81870592,82270905,81970742,82000764,82170868,and 81970731)The National Key R&D Program of China(grant 2018YFA0800600).
文摘Essential amino acids(EAAs)are crucial nutrients,whose levels change in rodents and patients with depression.However,how the levels of a single EAA affects depressive behaviors remains elusive.Here,we demonstrate that although deprivation of the EAA leucine has no effect in unstressed mice,it remarkably reverses the depression-like behaviors induced by chronic restraint stress(CRS).This beneficial effect is independent of feeding and is applicable to the dietary deficiency of other EAAs.Furthermore,the effect of leucine deprivation is suppressed by central injection of leucine or mimicked by central injection of leucinol.Moreover,hypothalamic agouti-related peptide(AgRP)neural activity changes during CRS and leucine deprivation,and chemogenetically inhibiting AgRP neurons eliminates the antidepressant effects of leucine deprivation.Finally,the leucine deprivation-regulated behavioral effects are mediated by amino acid sensor general control non-derepressible 2(GCN2)in AgRP neurons.Taken together,our results suggest a new drug target and/or dietary intervention for the reduction of depressive symptoms.
文摘色氨酸作为机体必需氨基酸,参与蛋白质合成,还通过5-羟色胺和犬尿氨酸代谢途径产生重要的活性化合物,诱导激活细胞内多种信号通路,在细胞生长、增殖以及代谢平衡等过程中发挥重要作用,且呈剂量依赖性。色氨酸可通过激活哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)、酪氨酸蛋白激酶2/信号转导与转录激活因子3(Janus kinase 2/signal transducer and activator of transcription 3,JAK2/STAT3)信号通路和一般性调控阻遏蛋白激酶2(general control non-derepressible 2,GCN2)经典应激反应促进细胞增殖;5-羟色胺经其受体(5-hydroxytryptamine receptor,5-HTR)和转运体(serotonin transporter,SETR)内化后激活下游信号分子,促进细胞增殖。然而高表达的吲哚胺-2,3-双加氧酶(indoleamine 2,3-dioxygenase,IDO)大量消耗色氨酸,导致色氨酸耗竭和代谢物大量累积,从而抑制细胞增殖;同时犬尿氨酸激活芳烃受体(aryl hydrocarbon receptor,AhR),阻滞细胞周期进程,抑制细胞增殖。该文综述了色氨酸代谢途径及其代谢物诱导的多种信号通路对细胞增殖的调控机理,旨在临床靶向治疗时,可通过精准地调控色氨酸代谢的限速酶来治疗由细胞异常增殖而引起的代谢性疾病。
基金Research from the corresponding author’s laboratory was supported by grants from the National Key Research and Development Program of China(No.2018YFA0800600)the National Natural Science Foundation of China(No.91957207,31830044,81870592,81770852,81700761,81700750,81970742,81970731,81570777 and 81600623)+1 种基金Basic Research Project of Shanghai Science and Technology Commission(No.16JC1404900,17XD1404200)CAS Interdisciplinary Innovation Team,Novo Nordisk-Chinese Academy of Sciences Research Fund(No.NNCAS-2008-10)。
文摘氨基酸是人必需的营养物质,具有广泛的生物学功能,它是蛋白质的组成单位,能量代谢物质。此外,它还作为信号分子广泛参与对多种生理功能的维持与调控,并在转录、翻译、翻译后修饰等多个层面上发挥作用。肝脏是关键的代谢器官,它充当连接各种组织代谢的枢纽。氨基酸感应在肝脏糖脂代谢的调控中起到十分重要的作用。因此准确地感应细胞内和细胞外氨基酸的水平,成为维持细胞内稳态的关键。真核细胞中存在一些众所周知的氨基酸感应因子,即一般性调控阻遏蛋白激酶2 (general control non-derepressible-2, GCN2)、哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)以及味觉受体等,在维持机体代谢稳态中发挥重要作用。本文对氨基酸调控肝脏糖脂代谢的作用与机制做了详细介绍,为进一步探究氨基酸感应机制以及治疗肝脏糖脂代谢紊乱疾病奠定了基础。
文摘From the conventional knowledge of protein nutrition to the molecular nutrition of amino acids, our understanding of protein/amino acid nutrition is rapidly increasing. Amino acids control cell growth and metabolism through two amino acid-sensingpathways, i.e. target of rapamycin complex 1 (TORC1) and the general control nonderepressible 2 (GCN2) signaling pathway.In the amino acid-abundant status, TORC1 dominates intracellular signaling and increases protein synthesis and cell growth.In contrast, amino acid deprivation actives GCN2 resulting in repression of general protein synthesis but facilitates the aminoacid transport and synthesis process. By integrating and coordinating nutrition and hormone signaling, TORC1 and GCN2control the switch of the catabolism and anabolism phase in most eukaryotes. Now, we appreciate that the availability ofindividual amino acids is sensed by intracellular sensors. These cutting-edge findings expand our knowledge of amino acidnutrition. Although the TORC1 and GCN2 were discovered decades ago, the study of molecular amino acid nutrition inaquaculture animals is still at its infancy. The aquaculture industry is highly dependent on the supply of fishmeal, which isthe major protein source in aquacultural animal diets. Some concerted efforts were conducted to substitute for fishmeal dueto limited supply of it. However, the concomitant issues including the unbalanced amino acid profile of alternative proteinsources limited the utilization of those proteins. Continued study of the molecular nutrition of amino acid in aquacultureanimals may be expected in the immediate future to expand our knowledge on the utilization of alternative protein sources.
基金funding by the National Institutes of Health grant HD070487the New Jersey Agricultural Extension Station and USDA NIFA NC1184 in support of work described in this article
文摘This article provides a brief overview describing how two key signaling pathways, namely the integrated stress response and the mammalian target of rapamycin complex 1, work together to facilitate cellular adaptation to dietary amino acid insufficiency. A deeper understanding of these mechanisms is leading to identification of novel targets which aid in disease treatments, improve stress recovery and increase health span through slowed aging and enhanced metabolic fitness.
