V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating ene...V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.展开更多
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
In the face of constantly changing environments,the central nervous system(CNS)rapidly and accurately calculates the body's needs,regulates feeding behavior,and maintains energy homeostasis.The arcuate nucleus of ...In the face of constantly changing environments,the central nervous system(CNS)rapidly and accurately calculates the body's needs,regulates feeding behavior,and maintains energy homeostasis.The arcuate nucleus of the hypothalamus(ARC)plays a key role in this process,serv-ing as a critical brain region for detecting nutrition-related hormones and regulating appetite and energy homeostasis.Agouti-related protein(AgRP)/neuropeptide Y(NPY)neu-rons in the ARC are core elements that interact with other brain regions through a complex appetite-regulating network to comprehensively control energy homeostasis.In this review,we explore the discovery and research progress of AgRP neurons in regulating feeding and energy metabolism.In addition,recent advances in terms of feeding behavior and energy homeostasis,along with the redundant neural mecha-nisms involved in energy metabolism,are discussed.Finally,the challenges and opportunities in the field of neural regula-tion of feeding and energy metabolism are briefly discussed.展开更多
脊椎动物下丘脑中的神经肽Y(Neuropeptide Y,NPY)、GALANIN和GMAP蛋白前体(GALANIN and GMAP prepropeptide,GAL)、Agouti相关蛋白(Agouti related neuropeptide,AGRP)和阿片促黑色素原(Proopiomelanocortin,POMC)与摄食密切相关,但在...脊椎动物下丘脑中的神经肽Y(Neuropeptide Y,NPY)、GALANIN和GMAP蛋白前体(GALANIN and GMAP prepropeptide,GAL)、Agouti相关蛋白(Agouti related neuropeptide,AGRP)和阿片促黑色素原(Proopiomelanocortin,POMC)与摄食密切相关,但在斑马鱼中对这些神经肽与摄食之间关系的研究较少。本文通过原位杂交技术和实时定量PCR方法,观察饥饿1 d、饥饿2 d和饥饿2 d喂食2 d后斑马鱼下丘脑中npy、galanin、agrp和pomca的表达情况。结果显示,饥饿处理之后,agrp和galanin在斑马鱼下丘脑中的表达量显著上升(P<0.05)。与对照组相比,饥饿2 d后斑马鱼下丘脑中pomca表达量显著下降(P<0.05)。饥饿2 d喂食2 d后斑马鱼下丘脑中pomca、agrp和galanin的表达量与对照组相比没有显著性差异。所有实验中npy在斑马鱼下丘脑中的表达没有显著性差异。这表明饥饿处理促使斑马鱼下丘脑中agrp和galanin表达上调,pomca表达下调;及时摄食可以恢复agrp、galanin和pomca在下丘脑中的表达水平。展开更多
基金support from various sources,including the National Natural Science Foundation of China(Grant Nos.81570774,82070872,92049118,and 82370854)the Junior Thousand Talents Program of China,and the Nanjing Medical University Startup Fund(All awarded to J.L.)support provided by Jiangsu Province's Innovation Personal as well as Innovative and Entrepreneurial Team of Jiangsu Province(Grant No.JSSCTD2021)(All awarded to J.L.).
文摘V-raf-leukemia viral oncogene 1(RAF1),a serine/threonine protein kinase,is well established to play a crucial role in tumorigenesis and cell development.However,the specific role of hypothalamic RAF1 in regulating energy metabolism remains unknown.In this study,we found that the expression of RAF1 was significantly increased in hypothalamic AgRP neurons of diet-induced obesity(DIO)mice.Under normal chow diet feeding,overexpression of Raf1 in AgRP neurons led to obesity in mice characterized by increased body weight,fat mass,and impaired glucose tolerance.Conversely,Raf1 knockout in AgRP neurons protected against diet-induced obesity,reducing fat mass and improving glucose tolerance.Mechanistically,Raf1 activated the MAPK signaling pathway,culminating in the phosphorylation of cAMP response element-binding protein(CREB),which enhanced transcription of Agrp and Npy.Insulin stimulation further potentiated the RAF1-MEK1/2-ERK1/2-CREB axis,highlighting RAF1's role in integrating hormonal and nutritional signals to regulate energy balance.Collectively,these findings underscore the important role of RAF1 in AgRP neurons in maintaining energy homeostasis and obesity pathogenesis,positioning it and its downstream pathways as potential therapeutic targets for innovative strategies to combat obesity and related metabolic diseases.
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.
基金supported by Grants from the Research Funds of the Center for Advanced Interdisciplinary Science and Biomedicine of IHM(QYPY20220018)the National Natural Science Foundation of China(31822026,32271063,31500860,and 32100821)the National Science and Technology Innovation 2030 Major Project of China(2021ZD0203900).
文摘In the face of constantly changing environments,the central nervous system(CNS)rapidly and accurately calculates the body's needs,regulates feeding behavior,and maintains energy homeostasis.The arcuate nucleus of the hypothalamus(ARC)plays a key role in this process,serv-ing as a critical brain region for detecting nutrition-related hormones and regulating appetite and energy homeostasis.Agouti-related protein(AgRP)/neuropeptide Y(NPY)neu-rons in the ARC are core elements that interact with other brain regions through a complex appetite-regulating network to comprehensively control energy homeostasis.In this review,we explore the discovery and research progress of AgRP neurons in regulating feeding and energy metabolism.In addition,recent advances in terms of feeding behavior and energy homeostasis,along with the redundant neural mecha-nisms involved in energy metabolism,are discussed.Finally,the challenges and opportunities in the field of neural regula-tion of feeding and energy metabolism are briefly discussed.
