Pub Date : 2024-12-03DOI: 10.1038/s42255-024-01168-8
Addison N. Webster, Jordan J. Becker, Chia Li, Dana C. Schwalbe, Damien Kerspern, Eva O. Karolczak, Catherine B. Bundon, Roberta A. Onoharigho, Maisie Crook, Maira Jalil, Elizabeth N. Godschall, Emily G. Dame, Adam Dawer, Dylan Matthew Belmont-Rausch, Tune H. Pers, Andrew Lutas, Naomi Habib, Ali D. Güler, Michael J. Krashes, John N. Campbell
Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite. Combining rabies-based connectomics with single-nucleus transcriptomics, the authors identify a neural circuit through which GLP-1 receptor agonists suppress appetite in mice.
{"title":"Molecular connectomics reveals a glucagon-like peptide 1-sensitive neural circuit for satiety","authors":"Addison N. Webster, Jordan J. Becker, Chia Li, Dana C. Schwalbe, Damien Kerspern, Eva O. Karolczak, Catherine B. Bundon, Roberta A. Onoharigho, Maisie Crook, Maira Jalil, Elizabeth N. Godschall, Emily G. Dame, Adam Dawer, Dylan Matthew Belmont-Rausch, Tune H. Pers, Andrew Lutas, Naomi Habib, Ali D. Güler, Michael J. Krashes, John N. Campbell","doi":"10.1038/s42255-024-01168-8","DOIUrl":"10.1038/s42255-024-01168-8","url":null,"abstract":"Liraglutide and other glucagon-like peptide 1 receptor agonists (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. One potential mechanism is by activating neurons that inhibit the hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc). To identify these afferents, we developed a method combining rabies-based connectomics with single-nucleus transcriptomics. Here, we identify at least 21 afferent subtypes of AgRP neurons in the mouse mediobasal and paraventricular hypothalamus, which are predicted by our method. Among these are thyrotropin-releasing hormone (TRH)+ Arc (TRHArc) neurons, inhibitory neurons that express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TRHArc neurons inhibits AgRP neurons and feeding, probably in an AgRP neuron-dependent manner. Silencing TRHArc neurons causes overeating and weight gain and attenuates liraglutide’s effect on body weight. Our results demonstrate a widely applicable method for molecular connectomics, comprehensively identify local inputs to AgRP neurons and reveal a circuit through which GLP-1RAs suppress appetite. Combining rabies-based connectomics with single-nucleus transcriptomics, the authors identify a neural circuit through which GLP-1 receptor agonists suppress appetite in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2354-2373"},"PeriodicalIF":18.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-26DOI: 10.1038/s42255-024-01166-w
Minwoo Nam, Wenxin Xia, Abdul Hannan Mir, Alexandra Jerrett, Jessica B. Spinelli, Tony T. Huang, Richard Possemato
Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy. Nam et al. show that limited glucose availability similar to the tumour microenvironment confers resistance against chemotherapeutic drugs that target DNA synthesis.
癌细胞由于增殖旺盛和肿瘤血管不足，往往会经历营养限制条件，从而产生新陈代谢适应以维持增殖。大多数癌细胞会迅速消耗葡萄糖，而在营养匮乏的肿瘤微环境中，葡萄糖会严重减少。通过基于 CRISPR 的基因筛选来确定受葡萄糖限制影响的代谢途径，我们发现与肿瘤相关的葡萄糖浓度（低糖）能保护癌细胞免受新嘧啶生物合成的抑制，而新嘧啶生物合成是化疗经常针对的途径。我们确定了两种机制来解释这一结果，并在各种癌症类型中广泛观察到这一结果。首先，低血糖限制了尿苷-5-二磷酸-葡萄糖的合成，保持了嘧啶核苷酸的可用性，从而延长了复制叉停滞的时间。其次，低糖通过抑制 BAK 激活和随后的细胞色素 c 释放（激活 caspase-9 依赖性线粒体凋亡的关键事件），直接调节复制叉失速下游的细胞凋亡。这些结果表明，在肿瘤中经常观察到的低血糖水平可能会限制特定化疗药物的疗效，突出了考虑肿瘤营养环境对癌症治疗影响的重要性。
{"title":"Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition","authors":"Minwoo Nam, Wenxin Xia, Abdul Hannan Mir, Alexandra Jerrett, Jessica B. Spinelli, Tony T. Huang, Richard Possemato","doi":"10.1038/s42255-024-01166-w","DOIUrl":"10.1038/s42255-024-01166-w","url":null,"abstract":"Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy. Nam et al. show that limited glucose availability similar to the tumour microenvironment confers resistance against chemotherapeutic drugs that target DNA synthesis.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2338-2353"},"PeriodicalIF":18.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1038/s42255-024-01157-x
Anna Castells-Nobau, Irene Puig, Anna Motger-Albertí, Lisset de la Vega-Correa, Marisel Rosell-Díaz, María Arnoriaga-Rodríguez, Anira Escrichs, Josep Garre-Olmo, Josep Puig, Rafael Ramos, Lluís Ramió-Torrentà, Vicente Pérez-Brocal, Andrés Moya, Reinald Pamplona, Mariona Jové, Joaquim Sol, Elena Martin-Garcia, Manuel Martinez-Garcia, Gustavo Deco, Rafael Maldonado, José Manuel Fernández-Real, Jordi Mayneris-Perxachs
Food addiction contributes to the obesity pandemic, but the connection between how the gut microbiome is linked to food addiction remains largely unclear. Here we show that Microviridae bacteriophages, particularly Gokushovirus WZ-2015a, are associated with food addiction and obesity across multiple human cohorts. Further analyses reveal that food addiction and Gokushovirus are linked to serotonin and dopamine metabolism. Mice receiving faecal microbiota and viral transplantation from human donors with the highest Gokushovirus load exhibit increased food addiction along with changes in tryptophan, serotonin and dopamine metabolism in different regions of the brain, together with alterations in dopamine receptors. Mechanistically, targeted tryptophan analysis shows lower anthranilic acid (AA) concentrations associated with Gokushovirus. AA supplementation in mice decreases food addiction and alters pathways related to the cycle of neurotransmitter synthesis release. In Drosophila, AA regulates feeding behaviour and addiction-like ethanol preference. In summary, this study proposes that bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism. Castells-Nobau et al. provide insight into how bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism in the host.
食物上瘾是肥胖症流行的原因之一，但肠道微生物组与食物上瘾之间的联系在很大程度上仍不清楚。在这里，我们发现微小病毒科噬菌体，尤其是Gokushovirus WZ-2015a，在多个人类队列中与食物成瘾和肥胖有关。进一步的分析表明，食物成瘾和 Gokushovirus 与血清素和多巴胺代谢有关。接受粪便微生物群和病毒移植的小鼠来自戈库舒病毒载量最高的人类捐献者，表现出食物成瘾性增加，同时大脑不同区域的色氨酸、血清素和多巴胺代谢发生变化，多巴胺受体也发生变化。从机理上讲，有针对性的色氨酸分析表明，与戈库什病毒有关的蚁酸（AA）浓度较低。在小鼠体内补充 AA 会降低食物成瘾性，并改变与神经递质合成释放周期相关的途径。在果蝇中，AA 可调节摄食行为和类似上瘾的乙醇偏好。总之，本研究提出，肠道微生物组中的噬菌体通过调节色氨酸和酪氨酸代谢，有助于调节食物成瘾。
{"title":"Microviridae bacteriophages influence behavioural hallmarks of food addiction via tryptophan and tyrosine signalling pathways","authors":"Anna Castells-Nobau, Irene Puig, Anna Motger-Albertí, Lisset de la Vega-Correa, Marisel Rosell-Díaz, María Arnoriaga-Rodríguez, Anira Escrichs, Josep Garre-Olmo, Josep Puig, Rafael Ramos, Lluís Ramió-Torrentà, Vicente Pérez-Brocal, Andrés Moya, Reinald Pamplona, Mariona Jové, Joaquim Sol, Elena Martin-Garcia, Manuel Martinez-Garcia, Gustavo Deco, Rafael Maldonado, José Manuel Fernández-Real, Jordi Mayneris-Perxachs","doi":"10.1038/s42255-024-01157-x","DOIUrl":"10.1038/s42255-024-01157-x","url":null,"abstract":"Food addiction contributes to the obesity pandemic, but the connection between how the gut microbiome is linked to food addiction remains largely unclear. Here we show that Microviridae bacteriophages, particularly Gokushovirus WZ-2015a, are associated with food addiction and obesity across multiple human cohorts. Further analyses reveal that food addiction and Gokushovirus are linked to serotonin and dopamine metabolism. Mice receiving faecal microbiota and viral transplantation from human donors with the highest Gokushovirus load exhibit increased food addiction along with changes in tryptophan, serotonin and dopamine metabolism in different regions of the brain, together with alterations in dopamine receptors. Mechanistically, targeted tryptophan analysis shows lower anthranilic acid (AA) concentrations associated with Gokushovirus. AA supplementation in mice decreases food addiction and alters pathways related to the cycle of neurotransmitter synthesis release. In Drosophila, AA regulates feeding behaviour and addiction-like ethanol preference. In summary, this study proposes that bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism. Castells-Nobau et al. provide insight into how bacteriophages in the gut microbiome contribute to regulating food addiction by modulating tryptophan and tyrosine metabolism in the host.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2157-2186"},"PeriodicalIF":18.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-25DOI: 10.1038/s42255-024-01164-y
Johanna Siehler, Sara Bilekova, Prisca Chapouton, Alessandro Dema, Pascal Albanese, Sem Tamara, Chirag Jain, Michael Sterr, Stephen J. Enos, Chunguang Chen, Chetna Malhotra, Adrian Villalba, Leopold Schomann, Sreya Bhattacharya, Jin Feng, Melis Akgün Canan, Federico Ribaudo, Ansarullah, Ingo Burtscher, Christin Ahlbrecht, Oliver Plettenburg, Thomas Kurth, Raphael Scharfmann, Stephan Speier, Richard A. Scheltema, Heiko Lickert
Blunted first-phase insulin secretion and insulin deficiency are indicators of β cell dysfunction and diabetes manifestation. Therefore, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β cell function. Here, we identify the insulin inhibitory receptor (inceptor; encoded by the gene IIR/ELAPOR1) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (SC)-derived islets, we show that IIR knockout (KO) results in enhanced SC β cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC β cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localizes to clathrin-coated vesicles close to the plasma membrane and in the trans-Golgi network as well as in secretory granules, where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases proinsulin and insulin content and improves SC β cell GSIS. Altogether, our findings reveal the basic mechanisms of β cell insulin turnover and identify inceptor as an insulin degradation receptor. The insulin inhibitory receptor (inceptor) is found to bind to insulin and to regulate insulin stores by directing proinsulin and insulin towards lysosomal degradation.
第一阶段胰岛素分泌减弱和胰岛素缺乏是β细胞功能障碍和糖尿病表现的指标。因此，了解调节胰岛素平衡的分子机制可能为补充胰岛素含量和恢复β细胞功能提供切入点。在这里，我们发现胰岛素抑制受体（inceptor；由基因 IIR/ELAPOR1 编码）是一种通过溶酶体降解调节胰岛素储存的胰岛素结合受体。我们利用人类诱导多能干细胞（SC）衍生的胰岛研究表明，IIR基因敲除（KO）可增强SCβ细胞的分化和存活。令人震惊的是，延长体外培养 IIR KO SC β 细胞的时间会导致胰岛素含量和葡萄糖刺激胰岛素分泌（GSIS）大大增加。我们发现，受体定位于接近质膜的凝集素包被囊泡和跨高尔基网络以及分泌颗粒中，它在其中充当分选受体，引导原胰岛素和胰岛素进入溶酶体降解。使用单克隆抗体靶向胰岛素受体可增加原胰岛素和胰岛素含量，改善SC β细胞的GSIS。总之，我们的研究结果揭示了β细胞胰岛素周转的基本机制，并确定受体是一种胰岛素降解受体。
{"title":"Inceptor binds to and directs insulin towards lysosomal degradation in β cells","authors":"Johanna Siehler, Sara Bilekova, Prisca Chapouton, Alessandro Dema, Pascal Albanese, Sem Tamara, Chirag Jain, Michael Sterr, Stephen J. Enos, Chunguang Chen, Chetna Malhotra, Adrian Villalba, Leopold Schomann, Sreya Bhattacharya, Jin Feng, Melis Akgün Canan, Federico Ribaudo, Ansarullah, Ingo Burtscher, Christin Ahlbrecht, Oliver Plettenburg, Thomas Kurth, Raphael Scharfmann, Stephan Speier, Richard A. Scheltema, Heiko Lickert","doi":"10.1038/s42255-024-01164-y","DOIUrl":"10.1038/s42255-024-01164-y","url":null,"abstract":"Blunted first-phase insulin secretion and insulin deficiency are indicators of β cell dysfunction and diabetes manifestation. Therefore, insights into molecular mechanisms that regulate insulin homeostasis might provide entry sites to replenish insulin content and restore β cell function. Here, we identify the insulin inhibitory receptor (inceptor; encoded by the gene IIR/ELAPOR1) as an insulin-binding receptor that regulates insulin stores by lysosomal degradation. Using human induced pluripotent stem cell (SC)-derived islets, we show that IIR knockout (KO) results in enhanced SC β cell differentiation and survival. Strikingly, extended in vitro culture of IIR KO SC β cells leads to greatly increased insulin content and glucose-stimulated insulin secretion (GSIS). We find that inceptor localizes to clathrin-coated vesicles close to the plasma membrane and in the trans-Golgi network as well as in secretory granules, where it acts as a sorting receptor to direct proinsulin and insulin towards lysosomal degradation. Targeting inceptor using a monoclonal antibody increases proinsulin and insulin content and improves SC β cell GSIS. Altogether, our findings reveal the basic mechanisms of β cell insulin turnover and identify inceptor as an insulin degradation receptor. The insulin inhibitory receptor (inceptor) is found to bind to insulin and to regulate insulin stores by directing proinsulin and insulin towards lysosomal degradation.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2374-2390"},"PeriodicalIF":18.9,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01164-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cushing’s syndrome is caused by an elevation of endogenous or pharmacologically administered glucocorticoids. Acyl coenzyme A binding protein (ACBP, encoded by the gene diazepam binding inhibitor, Dbi) stimulates food intake and lipo-anabolic reactions. Here we found that plasma ACBP/DBI concentrations were elevated in patients and mice with Cushing’s syndrome. We used several methods for ACBP/DBI inhibition in mice, namely, (1) induction of ACBP/DBI autoantibodies, (2) injection of a neutralizing monoclonal antibody, (3) body-wide or hepatocyte-specific knockout of the Dbi gene, (4) mutation of the ACBP/DBI receptor Gabrg2 and (5) injections of triiodothyronine or (6) the thyroid hormone receptor-β agonist resmetirom to block Dbi transcription. These six approaches abolished manifestations of Cushing’s syndrome such as increased food intake, weight gain, excessive adiposity, liver damage, hypertriglyceridaemia and type 2 diabetes. In conclusion, it appears that ACBP/DBI constitutes an actionable target that is causally involved in the development of Cushing’s syndrome. The authors highlight the role of acyl coenzyme A binding protein (encoded by DBI) in Cushing’s syndrome by using six different inhibition methods and mapping the physiological effects.
{"title":"Pathogenic role of acyl coenzyme A binding protein (ACBP) in Cushing’s syndrome","authors":"Hui Pan, Ai-Ling Tian, Hui Chen, Yifan Xia, Allan Sauvat, Stephanie Moriceau, Flavia Lambertucci, Omar Motiño, Liwei Zhao, Peng Liu, Misha Mao, Sijing Li, Shuai Zhang, Adrien Joseph, Sylvère Durand, Fanny Aprahamian, Zeyu Luo, Yang Ou, Zhe Shen, Enfu Xue, Yuhong Pan, Vincent Carbonnier, Gautier Stoll, Sabrina Forveille, Marion Leduc, Giulia Cerrato, Alexandra Cerone, Maria Chiara Maiuri, Frederic Castinetti, Thierry Brue, Hongsheng Wang, Yuting Ma, Isabelle Martins, Oliver Kepp, Guido Kroemer","doi":"10.1038/s42255-024-01170-0","DOIUrl":"10.1038/s42255-024-01170-0","url":null,"abstract":"Cushing’s syndrome is caused by an elevation of endogenous or pharmacologically administered glucocorticoids. Acyl coenzyme A binding protein (ACBP, encoded by the gene diazepam binding inhibitor, Dbi) stimulates food intake and lipo-anabolic reactions. Here we found that plasma ACBP/DBI concentrations were elevated in patients and mice with Cushing’s syndrome. We used several methods for ACBP/DBI inhibition in mice, namely, (1) induction of ACBP/DBI autoantibodies, (2) injection of a neutralizing monoclonal antibody, (3) body-wide or hepatocyte-specific knockout of the Dbi gene, (4) mutation of the ACBP/DBI receptor Gabrg2 and (5) injections of triiodothyronine or (6) the thyroid hormone receptor-β agonist resmetirom to block Dbi transcription. These six approaches abolished manifestations of Cushing’s syndrome such as increased food intake, weight gain, excessive adiposity, liver damage, hypertriglyceridaemia and type 2 diabetes. In conclusion, it appears that ACBP/DBI constitutes an actionable target that is causally involved in the development of Cushing’s syndrome. The authors highlight the role of acyl coenzyme A binding protein (encoded by DBI) in Cushing’s syndrome by using six different inhibition methods and mapping the physiological effects.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2281-2299"},"PeriodicalIF":18.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01170-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1038/s42255-024-01169-7
Mhairi Paul, Mark Nixon
Cushing’s syndrome, a condition of chronic glucocorticoid excess, disrupts metabolic homeostasis, driving fat redistribution and promoting insulin resistance. New research uses a series of elegant approaches to reveal acyl-CoA-binding protein (ACBP) as a mediator of the metabolic disturbances associated with elevated glucocorticoid levels in mice.
{"title":"ACBP orchestrates the metabolic phenotype in Cushing’s syndrome","authors":"Mhairi Paul, Mark Nixon","doi":"10.1038/s42255-024-01169-7","DOIUrl":"10.1038/s42255-024-01169-7","url":null,"abstract":"Cushing’s syndrome, a condition of chronic glucocorticoid excess, disrupts metabolic homeostasis, driving fat redistribution and promoting insulin resistance. New research uses a series of elegant approaches to reveal acyl-CoA-binding protein (ACBP) as a mediator of the metabolic disturbances associated with elevated glucocorticoid levels in mice.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2220-2221"},"PeriodicalIF":18.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-22DOI: 10.1038/s42255-024-01167-9
Mauricio Berriel Diaz, Maria Rohm, Stephan Herzig
Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or ‘wasting’ of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer. Here, we describe the metabolic changes contributing to body wasting in cachexia and explain how the entangled action of both tumour-derived and host-amplified processes induces these metabolic changes. We discuss energy homeostasis and possible ways that the presence of a tumour interferes with or hijacks physiological energy conservation pathways. In that context, we highlight the role played by metabolic cross-talk mechanisms in cachexia pathogenesis. Lastly, we elaborate on the challenges and opportunities in the treatment of this devastating paraneoplastic phenomenon that arise from the complex and multifaceted metabolic cross-talk mechanisms and provide a status on current and emerging therapeutic approaches. In this Review, the authors highlight cancer cachexia as a complex and multifactorial disorder, and discuss the underlying host-driven and tumour-driven metabolic changes, therapeutic opportunities and the pertinent challenges in the treatment of cancer cachexia.
{"title":"Cancer cachexia: multilevel metabolic dysfunction","authors":"Mauricio Berriel Diaz, Maria Rohm, Stephan Herzig","doi":"10.1038/s42255-024-01167-9","DOIUrl":"10.1038/s42255-024-01167-9","url":null,"abstract":"Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or ‘wasting’ of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer. Here, we describe the metabolic changes contributing to body wasting in cachexia and explain how the entangled action of both tumour-derived and host-amplified processes induces these metabolic changes. We discuss energy homeostasis and possible ways that the presence of a tumour interferes with or hijacks physiological energy conservation pathways. In that context, we highlight the role played by metabolic cross-talk mechanisms in cachexia pathogenesis. Lastly, we elaborate on the challenges and opportunities in the treatment of this devastating paraneoplastic phenomenon that arise from the complex and multifaceted metabolic cross-talk mechanisms and provide a status on current and emerging therapeutic approaches. In this Review, the authors highlight cancer cachexia as a complex and multifactorial disorder, and discuss the underlying host-driven and tumour-driven metabolic changes, therapeutic opportunities and the pertinent challenges in the treatment of cancer cachexia.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2222-2245"},"PeriodicalIF":18.9,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-21DOI: 10.1038/s42255-024-01162-0
Shu Feng, Na Xie, Yongzhen Liu, Chao Qin, Ali Can Savas, Ting-Yu Wang, Shutong Li, Youliang Rao, Alexandra Shambayate, Tsui-Fen Chou, Charles Brenner, Canhua Huang, Pinghui Feng
As obligate intracellular pathogens, viruses activate host metabolic enzymes to supply intermediates that support progeny production. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of salvage nicotinamide adenine dinucleotide (NAD+) synthesis, is an interferon-inducible protein that inhibits the replication of several RNA and DNA viruses through unknown mechanisms. Here, we show that NAMPT restricts herpes simplex virus type 1 (HSV-1) replication by impeding the virion incorporation of viral proteins owing to its phosphoribosyl-hydrolase (phosphoribosylase) activity, which is independent of the role of NAMPT in NAD+ synthesis. Proteomics analysis of HSV-1-infected cells identifies phosphoribosylated viral structural proteins, particularly glycoproteins and tegument proteins, which are de-phosphoribosylated by NAMPT in vitro and in cells. Chimeric and recombinant HSV-1 carrying phosphoribosylation-resistant mutations show that phosphoribosylation promotes the incorporation of structural proteins into HSV-1 virions and subsequent virus entry. Loss of NAMPT renders mice highly susceptible to HSV-1 infection. Our work describes an additional enzymatic activity of a metabolic enzyme in viral infection and host defence, offering a system to interrogate the roles of protein phosphoribosylation in metazoans. The NAD+ synthesis enzyme NAMPT is shown to possess additional enzymatic activity as a phosphoribosylase, which restricts the virion incorporation of viral proteins and underpins its antiviral effect
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Pub Date : 2024-11-20DOI: 10.1038/s42255-024-01158-w
Despite their abundance and despite being the most numerous biological entities on Earth, viruses remain one of the least understood components of the human microbiome. In our study, we show how Microviridae bacteriophages in the gut microbiome are associated with food addiction through changes in tryptophan, serotonin and dopamine metabolism.
{"title":"Microviridae bacteriophages in the gut microbiome and food addiction in humans","authors":"","doi":"10.1038/s42255-024-01158-w","DOIUrl":"10.1038/s42255-024-01158-w","url":null,"abstract":"Despite their abundance and despite being the most numerous biological entities on Earth, viruses remain one of the least understood components of the human microbiome. In our study, we show how Microviridae bacteriophages in the gut microbiome are associated with food addiction through changes in tryptophan, serotonin and dopamine metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2035-2036"},"PeriodicalIF":18.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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