Nature metabolism最新文献_第10页

Inceptor binds to and directs insulin towards lysosomal degradation in β cells 受体与β细胞中的胰岛素结合并引导胰岛素进入溶酶体降解

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-25 DOI: 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

{"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}

引用次数: 0

Pathogenic role of acyl coenzyme A binding protein (ACBP) in Cushing’s syndrome 酰基辅酶 A 结合蛋白（ACBP）在库欣综合征中的致病作用

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-22 DOI: 10.1038/s42255-024-01170-0

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

{"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}

引用次数: 0

ACBP orchestrates the metabolic phenotype in Cushing’s syndrome ACBP 协调库欣综合征的代谢表型

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-22 DOI: 10.1038/s42255-024-01169-7

Mhairi Paul, Mark Nixon

引用次数: 0

Cancer cachexia: multilevel metabolic dysfunction 癌症恶病质：多层次代谢功能障碍

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-22 DOI: 10.1038/s42255-024-01167-9

Mauricio Berriel Diaz, Maria Rohm, Stephan Herzig

{"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}

引用次数: 0

Cryptic phosphoribosylase activity of NAMPT restricts the virion incorporation of viral proteins NAMPT 的隐性磷酸核糖酶活性限制了病毒蛋白在病毒中的结合

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-21 DOI: 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

{"title":"Cryptic phosphoribosylase activity of NAMPT restricts the virion incorporation of viral proteins","authors":"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","doi":"10.1038/s42255-024-01162-0","DOIUrl":"10.1038/s42255-024-01162-0","url":null,"abstract":"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","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2300-2318"},"PeriodicalIF":18.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678635","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}

引用次数: 0

Microviridae bacteriophages in the gut microbiome and food addiction in humans 人类肠道微生物群中的微病毒科噬菌体与食物成瘾

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-20 DOI: 10.1038/s42255-024-01158-w

引用次数: 0

Human PERIOD3 variants lead to winter depression-like behaviours via glucocorticoid signalling 人类 PERIOD3 变体通过糖皮质激素信号导致类似冬季抑郁症的行为

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-11 DOI: 10.1038/s42255-024-01163-z

Qian Gao, Zhiwei Tang, Haili Wang, Maya Yamazaki, Jia Jiang, Ying-Hui Fu, Louis J. Ptacek, Luoying Zhang

{"title":"Human PERIOD3 variants lead to winter depression-like behaviours via glucocorticoid signalling","authors":"Qian Gao, Zhiwei Tang, Haili Wang, Maya Yamazaki, Jia Jiang, Ying-Hui Fu, Louis J. Ptacek, Luoying Zhang","doi":"10.1038/s42255-024-01163-z","DOIUrl":"10.1038/s42255-024-01163-z","url":null,"abstract":"Our brain adapts to seasonal changes. Mis-adaptations may lead to seasonal patterns in several psychiatric disorders, but we know little regarding the underlying mechanisms. Our previous work identified two variants in the human circadian clock gene PERIOD3 (PER3), that is, P415A and H417R, which are associated with winter depression, but whether and how these variants lead to the disorder remain to be characterized. Here we find that male mice carrying human P415A and H417R display winter depression-like behaviours that are caused by the actions of P415A and H417R in the adrenal gland. Systemic corticosterone level is downregulated in adaptation to shortening of day length, while P415A and H417R eliminate this downregulation by increasing corticosterone synthesis. Enhanced glucocorticoid signalling represses the transcription of Tph2, which encodes the rate-limiting enzyme of serotonin synthesis, leading to increased depression-like behaviours. Taken together, our findings unveil a mechanism according to which human variants contribute to seasonal mood traits. The authors show how genetic variants of the human circadian clock gene PER3 are related to winter depression. In mice, under shorter light exposure, such variants enhance glucocorticoid signalling, inhibiting serotonin production and leading to depression-like behaviours.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 12","pages":"2267-2280"},"PeriodicalIF":18.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597982","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}

引用次数: 0

AI-READI: rethinking AI data collection, preparation and sharing in diabetes research and beyond AI-READI：重新思考糖尿病研究及其他领域的人工智能数据收集、准备和共享问题

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-08 DOI: 10.1038/s42255-024-01165-x

AI-READI Consortium

引用次数: 0

Author Correction: Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells 作者更正：支链α-酮酸有氧激活血管细胞中的 HIF1α 信号。

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-05 DOI: 10.1038/s42255-024-01171-z

Wusheng Xiao, Nishith Shrimali, Niv Vigder, William M. Oldham, Clary B. Clish, Huamei He, Samantha J. Wong, Bradley M. Wertheim, Elena Arons, Marcia C. Haigis, Jane A. Leopold, Joseph Loscalzo

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A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes IL-10 信号在 1 型糖尿病毛细血管阻滞和认知障碍中的致病作用

IF 18.9 1区医学

Nature metabolism Pub Date : 2024-11-04 DOI: 10.1038/s42255-024-01159-9

Sorabh Sharma, Manjinder Cheema, Patrick L. Reeson, Kamal Narayana, Roobina Boghozian, Ana Paula Cota, Tara P. Brosschot, Rachael D. FitzPatrick, Jakob Körbelin, Lisa A. Reynolds, Craig E. Brown

{"title":"A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes","authors":"Sorabh Sharma, Manjinder Cheema, Patrick L. Reeson, Kamal Narayana, Roobina Boghozian, Ana Paula Cota, Tara P. Brosschot, Rachael D. FitzPatrick, Jakob Körbelin, Lisa A. Reynolds, Craig E. Brown","doi":"10.1038/s42255-024-01159-9","DOIUrl":"10.1038/s42255-024-01159-9","url":null,"abstract":"Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain in both sexes are prone to stalling, with blocks consisting primarily of erythrocytes in branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstruction, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice reversed these impairments. Chronic treatment of diabetic mice with IL-10 receptor neutralizing antibodies improved cerebral blood flow, increased capillary flux and diameter, downregulated haemostasis and cell adhesion-related gene expression, and reversed cognitive deficits. These data suggest that IL-10 signalling has an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment associated with type 1 diabetes. Interleukin-10 promotes the formation of microcirculatory defects in the brain associated with cognitive impairment in a mouse model of type 1 diabetes.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"6 11","pages":"2082-2099"},"PeriodicalIF":18.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01159-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574461","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}

引用次数: 0