IF 6.2 2区医学

Glia Pub Date : 2023-09-22 DOI: 10.1002/glia.24470

Ryan W Castro, Mikayla C Lopes, Lindsay M De Biase, Gregorio Valdez

{"title":"Aging spinal cord microglia become phenotypically heterogeneous and preferentially target motor neurons and their synapses","authors":"Ryan W Castro, Mikayla C Lopes, Lindsay M De Biase, Gregorio Valdez","doi":"10.1002/glia.24470","DOIUrl":"10.1002/glia.24470","url":null,"abstract":"Microglia have been found to acquire unique region-dependent deleterious features with age and diseases that contribute to neuronal dysfunction and degeneration in the brain. However, it remains unknown whether microglia exhibit similar phenotypic heterogeneity in the spinal cord. Here, we performed a regional analysis of spinal cord microglia in 3-, 16-, 23-, and 30-month-old mice. Using light and electron microscopy, we discovered that spinal cord microglia acquire an increasingly activated phenotype during the course of aging regardless of regional location. However, aging causes microglia in the ventral but not dorsal horn to lose their spatial organization. Aged ventral horn microglia also aggregate around the somata of motor neurons and increase their contacts with motor synapses, which have been shown to be lost with age. These findings suggest that microglia may affect the ability of motor neurons to receive and relay motor commands during aging. To generate additional insights about aging spinal cord microglia, we performed RNA-sequencing on FACS-isolated microglia from 3-, 18-, 22-, and 29-month-old mice. We found that spinal cord microglia acquire a similar transcriptional identity as those in the brain during aging that includes altered expression of genes with roles in microglia-neuron interactions and inflammation. By 29 months of age, spinal cord microglia exhibit additional and unique transcriptional changes known and predicted to cause senescence and to alter lysosomal and ribosomal regulation. Altogether, this work provides the foundation to target microglia to ameliorate aged-related changes in the spinal cord, and particularly on the motor circuit.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"206-221"},"PeriodicalIF":6.2,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41092763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

YAP and TAZ regulate remyelination in the central nervous system YAP和TAZ调节中枢神经系统的髓鞘再生

IF 6.2 2区医学

Glia Pub Date : 2023-09-19 DOI: 10.1002/glia.24467

Jiayue Hong, Julia M. Kirkland, Jenica Acheta, Leandro N. Marziali, Brianna Beck, Haley Jeanette, Urja Bhatia, Grace Davis, Jacob Herron, Clémence Roué, Charly Abi-Ghanem, M. Laura Feltri, Kristen L. Zuloaga, Marie E. Bechler, Yannick Poitelon, Sophie Belin

{"title":"YAP and TAZ regulate remyelination in the central nervous system","authors":"Jiayue Hong, Julia M. Kirkland, Jenica Acheta, Leandro N. Marziali, Brianna Beck, Haley Jeanette, Urja Bhatia, Grace Davis, Jacob Herron, Clémence Roué, Charly Abi-Ghanem, M. Laura Feltri, Kristen L. Zuloaga, Marie E. Bechler, Yannick Poitelon, Sophie Belin","doi":"10.1002/glia.24467","DOIUrl":"10.1002/glia.24467","url":null,"abstract":"Myelinating cells are sensitive to mechanical stimuli from their extracellular matrix. Ablation of YAP and TAZ mechanotransducers in Schwann cells abolishes the axon–Schwann cell recognition, myelination, and remyelination in the peripheral nervous system. It was unknown if YAP and TAZ are also required for myelination and remyelination in the central nervous system. Here we define the importance of oligodendrocyte (OL) YAP and TAZ in vivo, by specific deletion in oligodendroglial cells in adult OLs during myelin repair. Blocking YAP and TAZ expression in OL lineage cells did not affect animal viability or any major defects on OL maturation and myelination. However, using a mouse model of demyelination/remyelination, we demonstrate that YAP and TAZ modulate the capacity of OLs to remyelinate axons, particularly during the early stage of the repair process, when OL proliferation is most important. These results indicate that YAP and TAZ signaling is necessary for effective remyelination of the mouse brain.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"156-166"},"PeriodicalIF":6.2,"publicationDate":"2023-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24467","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10313067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel method of isolating nuclei of human oligodendrocyte precursor cells reveals substantial developmental changes in gene expression and H3K27ac histone modification 分离人少突胶质前体细胞细胞核的新方法揭示了基因表达和H3K27ac组蛋白修饰的实质性发育变化

IF 6.2 2区医学

Glia Pub Date : 2023-09-15 DOI: 10.1002/glia.24462

Alexey Kozlenkov, Ramu Vadukapuram, Ping Zhou, Peter Fam, Michael Wegner, Stella Dracheva

{"title":"Novel method of isolating nuclei of human oligodendrocyte precursor cells reveals substantial developmental changes in gene expression and H3K27ac histone modification","authors":"Alexey Kozlenkov, Ramu Vadukapuram, Ping Zhou, Peter Fam, Michael Wegner, Stella Dracheva","doi":"10.1002/glia.24462","DOIUrl":"10.1002/glia.24462","url":null,"abstract":"Oligodendrocyte precursor cells (OPCs) generate differentiated mature oligodendrocytes (MOs) during development. In adult brain, OPCs replenish MOs in adaptive plasticity, neurodegenerative disorders, and after trauma. The ability of OPCs to differentiate to MOs decreases with age and is compromised in disease. Here we explored the cell specific and age-dependent differences in gene expression and H3K27ac histone mark in these two cell types. H3K27ac is indicative of active promoters and enhancers. We developed a novel flow-cytometry-based approach to isolate OPC and MO nuclei from human postmortem brain and profiled gene expression and H3K27ac in adult and infant OPCs and MOs genome-wide. In adult brain, we detected extensive H3K27ac differences between the two cell types with high concordance between gene expression and epigenetic changes. Notably, the expression of genes that distinguish MOs from OPCs appears to be under a strong regulatory control by the H3K27ac modification in MOs but not in OPCs. Comparison of gene expression and H3K27ac between infants and adults uncovered numerous developmental changes in each cell type, which were linked to several biological processes, including cell proliferation and glutamate signaling. A striking example was a subset of histone genes that were highly active in infant samples but fully lost activity in adult brain. Our findings demonstrate a considerable rearrangement of the H3K27ac landscape that occurs during the differentiation of OPCs to MOs and during postnatal development of these cell types, which aligned with changes in gene expression. The uncovered regulatory changes justify further in-depth epigenetic studies of OPCs and MOs in development and disease.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"69-89"},"PeriodicalIF":6.2,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10243789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human iPSC-derived endothelial cells promote CNS remyelination via BDNF and mTORC1 pathway 人ipsc来源的内皮细胞通过BDNF和mTORC1途径促进中枢神经系统再髓鞘形成

IF 6.2 2区医学

Glia Pub Date : 2023-09-07 DOI: 10.1002/glia.24466

Dan Ma, Huiyuan Zhang, Le Yin, Hao Xu, Lida Wu, Rahul Shaji, Fatema Rezai, Ayesha Mulla, Sukhteerath Kaur, Shengjiang Tan, Boris Kysela, Yilong Wang, Zhiguo Chen, Chao Zhao, Yuchun Gu

{"title":"Human iPSC-derived endothelial cells promote CNS remyelination via BDNF and mTORC1 pathway","authors":"Dan Ma, Huiyuan Zhang, Le Yin, Hao Xu, Lida Wu, Rahul Shaji, Fatema Rezai, Ayesha Mulla, Sukhteerath Kaur, Shengjiang Tan, Boris Kysela, Yilong Wang, Zhiguo Chen, Chao Zhao, Yuchun Gu","doi":"10.1002/glia.24466","DOIUrl":"10.1002/glia.24466","url":null,"abstract":"Damage of myelin is a component of many diseases in the central nervous system (CNS). The activation and maturation of the quiescent oligodendrocyte progenitor cells (OPCs) are the crucial cellular processes for CNS remyelination, which is influenced by neuroinflammation in the lesion microenvironment. Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) have shown promise in restoring function in various preclinical animal models. Here we ask whether and whether transplantation of hiPSC-ECs could benefit remyelination in a mouse model of CNS demyelination. Our results show that in vitro, hiPSC-ECs increase OPC proliferation, migration and differentiation via secreted soluble factors including brain-derived neurotrophic factor (BDNF). hiPSC-ECs also promote the survival of oligodendrocyte lineage cells in vitro and in vivo. Transplantation of hiPSC-ECs into a toxin-induced demyelination lesion in mouse corpus callosum (CC) leads to increased density of oligodendrocyte lineage cells and level of myelin in demyelinated area, correlated with a decreased neuroinflammation and an increased proportion of pro-regenerative M2 phenotype in microglia/macrophages. The hiPSC-EC-exposed oligodendrocyte lineage cells showed significant increase in the level of phosphorylated S6 ribosomal protein (pS6) both in vitro and in vivo, indicating an involvement of mTORC1 pathway. These results suggest that hiPSC-ECs may benefit myelin protection and regeneration which providing a potential source of cell therapy for a wide range of diseases and injuries associated with myelin damage.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"133-155"},"PeriodicalIF":6.2,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24466","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chronic psychosocial stress triggers microglial-/macrophage-induced inflammatory responses leading to neuronal dysfunction and depressive-related behavior 慢性社会心理应激触发小胶质/巨噬细胞诱导的炎症反应，导致神经元功能障碍和抑郁相关行为

IF 6.2 2区医学

Glia Pub Date : 2023-09-07 DOI: 10.1002/glia.24464

Alexandros G. Kokkosis, Miguel M. Madeira, Zachary Hage, Kimonas Valais, Dimitris Koliatsis, Emran Resutov, Stella E. Tsirka

{"title":"Chronic psychosocial stress triggers microglial-/macrophage-induced inflammatory responses leading to neuronal dysfunction and depressive-related behavior","authors":"Alexandros G. Kokkosis, Miguel M. Madeira, Zachary Hage, Kimonas Valais, Dimitris Koliatsis, Emran Resutov, Stella E. Tsirka","doi":"10.1002/glia.24464","DOIUrl":"10.1002/glia.24464","url":null,"abstract":"Chronic environmental stress and traumatic social experiences induce maladaptive behavioral changes and is a risk factor for major depressive disorder (MDD) and various anxiety-related psychiatric disorders. Clinical studies and animal models of chronic stress have reported that symptom severity is correlated with innate immune responses and upregulation of neuroinflammatory cytokine signaling in brain areas implicated in mood regulation (mPFC; medial Prefrontal Cortex). Despite increasing evidence implicating impairments of neuroplasticity and synaptic signaling deficits into the pathophysiology of stress-related mental disorders, how microglia may modulate neuronal homeostasis in response to chronic stress has not been defined. Here, using the repeated social defeat stress (RSDS) mouse model we demonstrate that microglial-induced inflammatory responses are regulating neuronal plasticity associated with psychosocial stress. Specifically, we show that chronic stress induces a rapid activation and proliferation of microglia as well as macrophage infiltration in the mPFC, and these processes are spatially related to neuronal activation. Moreover, we report a significant association of microglial inflammatory responses with susceptibility or resilience to chronic stress. In addition, we find that exposure to chronic stress exacerbates phagocytosis of synaptic elements and deficits in neuronal plasticity. Importantly, by utilizing two different CSF1R inhibitors (the brain penetrant PLX5622 and the non-penetrant PLX73086) we highlight a crucial role for microglia (and secondarily macrophages) in catalyzing the pathological manifestations linked to psychosocial stress in the mPFC and the resulting behavioral deficits usually associated with depression.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"111-132"},"PeriodicalIF":6.2,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10173503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cover Image, Volume 71, Issue 11 封面图片，第71卷，第11期

IF 6.2 2区医学

Glia Pub Date : 2023-09-05 DOI: 10.1002/glia.24214

Tenna Bering, Camilla Gadgaard, Henrik Vorum, Bent Honoré, Martin Fredensborg Rath

引用次数: 0

Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis 神经节苷脂GD3调节神经干细胞静止并控制出生后神经发生

IF 6.2 2区医学

Glia Pub Date : 2023-09-05 DOI: 10.1002/glia.24468

Takahiro Fuchigami, Yutaka Itokazu, Robert K. Yu

{"title":"Ganglioside GD3 regulates neural stem cell quiescence and controls postnatal neurogenesis","authors":"Takahiro Fuchigami, Yutaka Itokazu, Robert K. Yu","doi":"10.1002/glia.24468","DOIUrl":"10.1002/glia.24468","url":null,"abstract":"The postnatal neural stem cell (NSC) pool hosts quiescent and activated radial glia-like NSCs contributing to neurogenesis throughout adulthood. However, the underlying regulatory mechanism during the transition from quiescent NSCs to activated NSCs in the postnatal NSC niche is not fully understood. Lipid metabolism and lipid composition play important roles in regulating NSC fate determination. Biological lipid membranes define the individual cellular shape and help maintain cellular organization and are highly heterogeneous in structure and there exist diverse microdomains (also known as lipid rafts), which are enriched with sugar molecules, such as glycosphingolipids. An often overlooked but key aspect is that the functional activities of proteins and genes are highly dependent on their molecular environments. We previously reported that ganglioside GD3 is the predominant species in NSCs and that the reduced postnatal NSC pools are observed in global GD3-synthase knockout (GD3S-KO) mouse brains. The specific roles of GD3 in determining the stage and cell-lineage determination of NSCs remain unclear, since global GD3S-KO mice cannot distinguish if GD3 regulates postnatal neurogenesis or developmental impacts. Here, we show that inducible GD3 deletion in postnatal radial glia-like NSCs promotes NSC activation, resulting in the loss of the long-term maintenance of the adult NSC pools. The reduced neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of GD3S-conditional-knockout mice led to the impaired olfactory and memory functions. Thus, our results provide convincing evidence that postnatal GD3 maintains the quiescent state of radial glia-like NSCs in the adult NSC niche.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"167-183"},"PeriodicalIF":6.2,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10197774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

ApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes ApoE4的表达破坏了星形胶质细胞中tau的摄取、运输和清除

IF 6.2 2区医学

Glia Pub Date : 2023-09-05 DOI: 10.1002/glia.24469

Maxwell Eisenbaum, Andrew Pearson, Camila Ortiz, Michael Mullan, Fiona Crawford, Joseph Ojo, Corbin Bachmeier

{"title":"ApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes","authors":"Maxwell Eisenbaum, Andrew Pearson, Camila Ortiz, Michael Mullan, Fiona Crawford, Joseph Ojo, Corbin Bachmeier","doi":"10.1002/glia.24469","DOIUrl":"10.1002/glia.24469","url":null,"abstract":"Tauopathies are a collection of neurodegenerative diseases characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau. Despite the prevalence and diversity of tau astrogliopathy in tauopathies, the interactions between astrocytes and tau in the brain, and the influence of neurodegenerative genetic risk factors like the apolipoprotein E4 (apoE4) isoform, are largely unknown. Here, we leveraged primary and immortalized astrocytes expressing humanized apoE isoforms to characterize the mechanisms by which astrocytes interact with and eliminate extracellular tau, and the influence of apoE genotype on these processes. Our work indicates that astrocytes rapidly internalize, process, and release tau via an exosomal secretory mechanism under physiological conditions. However, we found that apoE4 disrupted these processes in comparison to apoE3, resulting in an astrocytic phenotype prone to intracellular tau accumulation. Furthermore, exposure to repetitive mild traumatic brain injuries exacerbated the apoE4-induced impairments in tau processing and elimination by astrocytes in apoE4 targeted-replacement mice. The diminished ability of apoE4 astrocytes to eliminate extracellular tau can lead to an accumulation of pathogenic tau, which induces mitochondrial dysfunction, as demonstrated by our studies. In total, our findings suggest that the apoE4 isoform lowers the threshold of astrocytic resilience to pathogenic tau, rendering them susceptible to bioenergetic deficits in the early stages of neurodegenerative diseases such as traumatic brain injury, potentially contributing to neurological decline.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"184-205"},"PeriodicalIF":6.2,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10153964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibiting astrocyte connexin-43 hemichannels blocks radiation-induced vesicular VEGF-A release and blood–brain barrier dysfunction 抑制星形胶质细胞连接蛋白43半通道阻断辐射诱导的囊泡VEGF-A释放和血脑屏障功能障碍

IF 6.2 2区医学

Glia Pub Date : 2023-09-05 DOI: 10.1002/glia.24460

Steffi Schumacher, Hanane Tahiri, Pascal Ezan, Nathalie Rouach, Katja Witschas, Luc Leybaert

{"title":"Inhibiting astrocyte connexin-43 hemichannels blocks radiation-induced vesicular VEGF-A release and blood–brain barrier dysfunction","authors":"Steffi Schumacher, Hanane Tahiri, Pascal Ezan, Nathalie Rouach, Katja Witschas, Luc Leybaert","doi":"10.1002/glia.24460","DOIUrl":"10.1002/glia.24460","url":null,"abstract":"Therapeutic brain irradiation with ionizing radiation exerts multiple side effects including barrier leakage that disturbs glial-neuronal functioning and may affect cognition. Astrocytes contribute to barrier leakage by endfeet release of various vasoactive substances acting on capillary endothelial cells forming the barrier. Here, we investigated X-ray effects on astrocytic vesicular transport in mice and determined whether interfering with astrocyte connexins affects radiation-induced barrier leakage. We found that astrocytic VEGF-A-loaded VAMP3 vesicles drastically reorganize starting from 6 h post-irradiation and move in a calcium- and Cx43-dependent manner towards endfeet where VEGF-A is released, provoking barrier leakage. Vesicular transport activation, VEGF-A release and leakage 24 h post-irradiation were all potently inhibited by astrocytic Cx43 KO, Cx43S255/262/279/282A (MK4) mutant mice and TATGap19 inhibition of Cx43 hemichannel opening. Astrocyte VEGF release is a major player in complications of brain irradiation, which can be mitigated by anti-VEGF treatments. Targeting Cx43 hemichannels allows to prevent astrocyte VEGF release at an early stage after brain irradiation.","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"34-50"},"PeriodicalIF":6.2,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10534275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Astrocytic FoxO1 in the hypothalamus regulates metabolic homeostasis by coordinating neuropeptide Y neuron activity 下丘脑中的星形细胞FoxO1通过协调神经肽Y神经元的活动来调节代谢稳态。

IF 6.2 2区医学

Glia Pub Date : 2023-09-01 DOI: 10.1002/glia.24448

Khanh Van Doan, Le Trung Tran, Dong Joo Yang, Thu Thi Anh Ha, Thi Dang Mai, Seul Ki Kim, Ronald A. DePinho, Dong-Min Shin, Yun-Hee Choi, Ki Woo Kim

{"title":"Astrocytic FoxO1 in the hypothalamus regulates metabolic homeostasis by coordinating neuropeptide Y neuron activity","authors":"Khanh Van Doan, Le Trung Tran, Dong Joo Yang, Thu Thi Anh Ha, Thi Dang Mai, Seul Ki Kim, Ronald A. DePinho, Dong-Min Shin, Yun-Hee Choi, Ki Woo Kim","doi":"10.1002/glia.24448","DOIUrl":"10.1002/glia.24448","url":null,"abstract":"The forkhead box transcription factor O1 (FoxO1) is expressed ubiquitously throughout the central nervous system, including in astrocytes, the most prevalent glial cell type in the brain. While the role of FoxO1 in hypothalamic neurons in controlling food intake and energy balance is well-established, the contribution of astrocytic FoxO1 in regulating energy homeostasis has not yet been determined. In the current study, we demonstrate the essential role of hypothalamic astrocytic FoxO1 in maintaining normal neuronal activity in the hypothalamus and whole-body glucose metabolism. Inhibition of FoxO1 function in hypothalamic astrocytes shifts the cellular metabolism from glycolysis to oxidative phosphorylation, enhancing astrocyte ATP production and release meanwhile decreasing astrocytic export of lactate. As a result, specific deletion of astrocytic FoxO1, particularly in the hypothalamus, causes a hyperactivation of hypothalamic neuropeptide Y neurons, which leads to an increase in acute feeding and impaired glucose regulation and ultimately results in diet-induced obesity and systemic glucose dyshomeostasis.","PeriodicalId":174,"journal":{"name":"Glia","volume":"71 12","pages":"2735-2752"},"PeriodicalIF":6.2,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24448","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10120343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

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