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
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。
