Pub Date : 2024-09-02DOI: 10.1038/s42255-024-01125-5
Ritsuko Nakai, Stella Varnum, Rachael L. Field, Henyun Shi, Rocky Giwa, Wentong Jia, Samantha J. Krysa, Eva F. Cohen, Nicholas Borcherding, Russell P. Saneto, Rick C. Tsai, Masashi Suganuma, Hisashi Ohta, Takafumi Yokota, Jonathan R. Brestoff
Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1–3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4−/− peritoneal macrophages4–7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10–12, brain13–15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4−/− mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4−/− mice, whereas mitochondria from Ndufs4−/− mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4−/− mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS. Administration of exogenous mitochondria from mice or humans, or stimulation of mitochondria transfer from haematopoietic cells through bone marrow transplant from wild-type mice, is shown to improve morbidity and mortality in a mouse model of the mitochondrial disease Leigh syndrome.
{"title":"Mitochondria transfer-based therapies reduce the morbidity and mortality of Leigh syndrome","authors":"Ritsuko Nakai, Stella Varnum, Rachael L. Field, Henyun Shi, Rocky Giwa, Wentong Jia, Samantha J. Krysa, Eva F. Cohen, Nicholas Borcherding, Russell P. Saneto, Rick C. Tsai, Masashi Suganuma, Hisashi Ohta, Takafumi Yokota, Jonathan R. Brestoff","doi":"10.1038/s42255-024-01125-5","DOIUrl":"10.1038/s42255-024-01125-5","url":null,"abstract":"Mitochondria transfer is a recently described phenomenon in which donor cells deliver mitochondria to acceptor cells1–3. One possible consequence of mitochondria transfer is energetic support of neighbouring cells; for example, exogenous healthy mitochondria can rescue cell-intrinsic defects in mitochondrial metabolism in cultured ρ0 cells or Ndufs4−/− peritoneal macrophages4–7. Exposing haematopoietic stem cells to purified mitochondria before autologous haematopoietic stem cell transplantation allowed for treatment of anaemia in patients with large-scale mitochondrial DNA mutations8,9, and mitochondria transplantation was shown to minimize ischaemic damage to the heart10–12, brain13–15 and limbs16. However, the therapeutic potential of using mitochondria transfer-based therapies to treat inherited mitochondrial diseases is unclear. Here we demonstrate improved morbidity and mortality of the Ndufs4−/− mouse model of Leigh syndrome (LS) in multiple treatment paradigms associated with mitochondria transfer. Transplantation of bone marrow from wild-type mice, which is associated with release of haematopoietic cell-derived extracellular mitochondria into circulation and transfer of mitochondria to host cells in multiple organs, ameliorates LS in mice. Furthermore, administering isolated mitochondria from wild-type mice extends lifespan, improves neurological function and increases energy expenditure of Ndufs4−/− mice, whereas mitochondria from Ndufs4−/− mice did not improve neurological function. Finally, we demonstrate that cross-species administration of human mitochondria to Ndufs4−/− mice also improves LS. These data suggest that mitochondria transfer-related approaches can be harnessed to treat mitochondrial diseases, such as LS. Administration of exogenous mitochondria from mice or humans, or stimulation of mitochondria transfer from haematopoietic cells through bone marrow transplant from wild-type mice, is shown to improve morbidity and mortality in a mouse model of the mitochondrial disease Leigh syndrome.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142118122","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 : 2024-08-29DOI: 10.1038/s42255-024-01119-3
Nina Grankvist, Cecilia Jönsson, Karin Hedin, Nicolas Sundqvist, Per Sandström, Bergthor Björnsson, Arjana Begzati, Evgeniya Mickols, Per Artursson, Mohit Jain, Gunnar Cedersund, Roland Nilsson
Liver metabolism is central to human physiology and influences the pathogenesis of common metabolic diseases. Yet, our understanding of human liver metabolism remains incomplete, with much of current knowledge based on animal or cell culture models that do not fully recapitulate human physiology. Here, we perform in-depth measurement of metabolism in intact human liver tissue ex vivo using global 13C tracing, non-targeted mass spectrometry and model-based metabolic flux analysis. Isotope tracing allowed qualitative assessment of a wide range of metabolic pathways within a single experiment, confirming well-known features of liver metabolism but also revealing unexpected metabolic activities such as de novo creatine synthesis and branched-chain amino acid transamination, where human liver appears to differ from rodent models. Glucose production ex vivo correlated with donor plasma glucose, suggesting that cultured liver tissue retains individual metabolic phenotypes, and could be suppressed by postprandial levels of nutrients and insulin, and also by pharmacological inhibition of glycogen utilization. Isotope tracing ex vivo allows measuring human liver metabolism with great depth and resolution in an experimentally tractable system. Grankvist et al. combine global isotopic tracing and metabolic flux modelling to characterize metabolic networks in human intact liver tissue.
{"title":"Global 13C tracing and metabolic flux analysis of intact human liver tissue ex vivo","authors":"Nina Grankvist, Cecilia Jönsson, Karin Hedin, Nicolas Sundqvist, Per Sandström, Bergthor Björnsson, Arjana Begzati, Evgeniya Mickols, Per Artursson, Mohit Jain, Gunnar Cedersund, Roland Nilsson","doi":"10.1038/s42255-024-01119-3","DOIUrl":"10.1038/s42255-024-01119-3","url":null,"abstract":"Liver metabolism is central to human physiology and influences the pathogenesis of common metabolic diseases. Yet, our understanding of human liver metabolism remains incomplete, with much of current knowledge based on animal or cell culture models that do not fully recapitulate human physiology. Here, we perform in-depth measurement of metabolism in intact human liver tissue ex vivo using global 13C tracing, non-targeted mass spectrometry and model-based metabolic flux analysis. Isotope tracing allowed qualitative assessment of a wide range of metabolic pathways within a single experiment, confirming well-known features of liver metabolism but also revealing unexpected metabolic activities such as de novo creatine synthesis and branched-chain amino acid transamination, where human liver appears to differ from rodent models. Glucose production ex vivo correlated with donor plasma glucose, suggesting that cultured liver tissue retains individual metabolic phenotypes, and could be suppressed by postprandial levels of nutrients and insulin, and also by pharmacological inhibition of glycogen utilization. Isotope tracing ex vivo allows measuring human liver metabolism with great depth and resolution in an experimentally tractable system. Grankvist et al. combine global isotopic tracing and metabolic flux modelling to characterize metabolic networks in human intact liver tissue.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01119-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090099","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 : 2024-08-27DOI: 10.1038/s42255-024-01096-7
Richard Possemato
Resistance to glutamine restriction is mediated by increased serine synthesis. The high affinity of serine synthesis enzyme PSAT1 for glutamate drives sustained glutamine utilization. Combined pathway targeting limits tumour growth in mouse breast cancer models.
{"title":"Affinity war: PSAT1 outcompetes the rest","authors":"Richard Possemato","doi":"10.1038/s42255-024-01096-7","DOIUrl":"10.1038/s42255-024-01096-7","url":null,"abstract":"Resistance to glutamine restriction is mediated by increased serine synthesis. The high affinity of serine synthesis enzyme PSAT1 for glutamate drives sustained glutamine utilization. Combined pathway targeting limits tumour growth in mouse breast cancer models.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081020","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 : 2024-08-27DOI: 10.1038/s42255-024-01104-w
Yijian Qiu, Olivia T. Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S. H. Costa, Sara Violante, David L. Spector, Justin R. Cross, Michael J. Lukey
Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism. Qiu et al. provide insight into the metabolic adaptations that enable breast cancer cells to proliferate in the face of glutaminolysis blockade.
{"title":"The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade","authors":"Yijian Qiu, Olivia T. Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S. H. Costa, Sara Violante, David L. Spector, Justin R. Cross, Michael J. Lukey","doi":"10.1038/s42255-024-01104-w","DOIUrl":"10.1038/s42255-024-01104-w","url":null,"abstract":"Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism. Qiu et al. provide insight into the metabolic adaptations that enable breast cancer cells to proliferate in the face of glutaminolysis blockade.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081022","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 : 2024-08-27DOI: 10.1038/s42255-024-01123-7
Although Western societies are mesmerized by the power of new anti-obesity drugs, we must not forget how diet can affect metabolic outcomes. In this Focus issue, and accompanying web collection, we showcase a series of Reviews, Comments and original research articles that present up-to-date evidence on how dietary interventions can affect cardiometabolic health.
{"title":"Feeding into cardiometabolic health","authors":"","doi":"10.1038/s42255-024-01123-7","DOIUrl":"10.1038/s42255-024-01123-7","url":null,"abstract":"Although Western societies are mesmerized by the power of new anti-obesity drugs, we must not forget how diet can affect metabolic outcomes. In this Focus issue, and accompanying web collection, we showcase a series of Reviews, Comments and original research articles that present up-to-date evidence on how dietary interventions can affect cardiometabolic health.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01123-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081021","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 : 2024-08-26DOI: 10.1038/s42255-024-01112-w
Daniel Stephen Lark, Kerstin Stemmer, Wei Ying, Clair Crewe
Extracellular vesicles (EVs) are now recognized as powerful modulators of metabolism, and thus the new field of EV-mediated metabolic regulation is growing exponentially. Here, we discuss special experimental considerations for the study of EV function in metabolism.
细胞外囊泡（EVs）现已被公认为是新陈代谢的强大调节剂，因此，EV介导的新陈代谢调节领域正呈指数级增长。在此，我们将讨论研究 EV 在新陈代谢中功能的特殊实验注意事项。
{"title":"A brief guide to studying extracellular vesicle function in the context of metabolism","authors":"Daniel Stephen Lark, Kerstin Stemmer, Wei Ying, Clair Crewe","doi":"10.1038/s42255-024-01112-w","DOIUrl":"10.1038/s42255-024-01112-w","url":null,"abstract":"Extracellular vesicles (EVs) are now recognized as powerful modulators of metabolism, and thus the new field of EV-mediated metabolic regulation is growing exponentially. Here, we discuss special experimental considerations for the study of EV function in metabolism.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073338","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 : 2024-08-22DOI: 10.1038/s42255-024-01108-6
Elizabeth Schneider, Kenneth J. O’Riordan, Gerard Clarke, John F. Cryan
The prevalence of brain disorders, including stress-related neuropsychiatric disorders and conditions with cognitive dysfunction, is rising. Poor dietary habits contribute substantially to this accelerating trend. Conversely, healthy dietary intake supports mood and cognitive performance. Recently, the communication between the microorganisms within the gastrointestinal tract and the brain along the gut–brain axis has gained prominence as a potential tractable target to modulate brain health. The composition and function of the gut microbiota is robustly influenced by dietary factors to alter gut–brain signalling. To reflect this interconnection between diet, gut microbiota and brain functioning, we propose that a diet–microbiota–gut–brain axis exists that underpins health and well-being. In this Review, we provide a comprehensive overview of the interplay between diet and gut microbiota composition and function and the implications for cognition and emotional functioning. Important diet-induced effects on the gut microbiota for the development, prevention and maintenance of neuropsychiatric disorders are described. The diet–microbiota–gut–brain axis represents an uncharted frontier for brain health diagnostics and therapeutics across the lifespan. This Review provides an overview of the interplay between host diet and the gut microbiota, and how this affects brain function.
{"title":"Feeding gut microbes to nourish the brain: unravelling the diet–microbiota–gut–brain axis","authors":"Elizabeth Schneider, Kenneth J. O’Riordan, Gerard Clarke, John F. Cryan","doi":"10.1038/s42255-024-01108-6","DOIUrl":"10.1038/s42255-024-01108-6","url":null,"abstract":"The prevalence of brain disorders, including stress-related neuropsychiatric disorders and conditions with cognitive dysfunction, is rising. Poor dietary habits contribute substantially to this accelerating trend. Conversely, healthy dietary intake supports mood and cognitive performance. Recently, the communication between the microorganisms within the gastrointestinal tract and the brain along the gut–brain axis has gained prominence as a potential tractable target to modulate brain health. The composition and function of the gut microbiota is robustly influenced by dietary factors to alter gut–brain signalling. To reflect this interconnection between diet, gut microbiota and brain functioning, we propose that a diet–microbiota–gut–brain axis exists that underpins health and well-being. In this Review, we provide a comprehensive overview of the interplay between diet and gut microbiota composition and function and the implications for cognition and emotional functioning. Important diet-induced effects on the gut microbiota for the development, prevention and maintenance of neuropsychiatric disorders are described. The diet–microbiota–gut–brain axis represents an uncharted frontier for brain health diagnostics and therapeutics across the lifespan. This Review provides an overview of the interplay between host diet and the gut microbiota, and how this affects brain function.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142022187","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 : 2024-08-21DOI: 10.1038/s42255-024-01114-8
Marta Perez-Frances, Eva Bru-Tari, Christian Cohrs, Maria Valentina Abate, Léon van Gurp, Kenichiro Furuyama, Stephan Speier, Fabrizio Thorel, Pedro L. Herrera
Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing ‘non-β-cells’ (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ. Pancreatic islet β-cells can regulate insulin secretion in vivo, even in the absence of non-β-cells.
{"title":"Regulated and adaptive in vivo insulin secretion from islets only containing β-cells","authors":"Marta Perez-Frances, Eva Bru-Tari, Christian Cohrs, Maria Valentina Abate, Léon van Gurp, Kenichiro Furuyama, Stephan Speier, Fabrizio Thorel, Pedro L. Herrera","doi":"10.1038/s42255-024-01114-8","DOIUrl":"10.1038/s42255-024-01114-8","url":null,"abstract":"Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing ‘non-β-cells’ (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ. Pancreatic islet β-cells can regulate insulin secretion in vivo, even in the absence of non-β-cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01114-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018098","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 : 2024-08-21DOI: 10.1038/s42255-024-01117-5
Pancreatic β-cells do not appear to require interactions with neighbouring non-β-cells (α-cells, δ-cells and γ-cells) to regulate insulin secretion. These results are clinically relevant and support the development of treatments for diabetes that involve the generation of β-like cells alone, whether from pluripotent cells or by in situ conversion of non-β-cells.
{"title":"Regulated insulin secretion from human and mouse islets exclusively composed of β-cells","authors":"","doi":"10.1038/s42255-024-01117-5","DOIUrl":"10.1038/s42255-024-01117-5","url":null,"abstract":"Pancreatic β-cells do not appear to require interactions with neighbouring non-β-cells (α-cells, δ-cells and γ-cells) to regulate insulin secretion. These results are clinically relevant and support the development of treatments for diabetes that involve the generation of β-like cells alone, whether from pluripotent cells or by in situ conversion of non-β-cells.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018099","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 : 2024-08-20DOI: 10.1038/s42255-024-01106-8
Faidon Magkos, Thorkild I. A. Sørensen, David Raubenheimer, Nikhil V. Dhurandhar, Ruth J. F. Loos, Anja Bosy-Westphal, Christoffer Clemmensen, Mads F. Hjorth, David B. Allison, Gary Taubes, Eric Ravussin, Mark I. Friedman, Kevin D. Hall, David S. Ludwig, John R. Speakman, Arne Astrup
Application of the physical laws of energy and mass conservation at the whole-body level is not necessarily informative about causal mechanisms of weight gain and the development of obesity. The energy balance model (EBM) and the carbohydrate–insulin model (CIM) are two plausible theories, among several others, attempting to explain why obesity develops within an overall common physiological framework of regulation of human energy metabolism. These models have been used to explain the pathogenesis of obesity in individuals as well as the dramatic increases in the prevalence of obesity worldwide over the past half century. Here, we summarize outcomes of a recent workshop in Copenhagen that brought together obesity experts from around the world to discuss causal models of obesity pathogenesis. These discussions helped to operationally define commonly used terms; delineate the structure of each model, particularly focussing on areas of overlap and divergence; challenge ideas about the importance of purported causal factors for weight gain; and brainstorm on the key scientific questions that need to be answered. We hope that more experimental research in nutrition and other related fields, and more testing of the models and their predictions will pave the way and provide more answers about the pathogenesis of obesity than those currently available. This authoritative Perspective lays a foundation for the field of obesity research by comparing commonalities and differences between competing models of obesity pathogenesis and by defining terms that are at the core of this discussion.
{"title":"On the pathogenesis of obesity: causal models and missing pieces of the puzzle","authors":"Faidon Magkos, Thorkild I. A. Sørensen, David Raubenheimer, Nikhil V. Dhurandhar, Ruth J. F. Loos, Anja Bosy-Westphal, Christoffer Clemmensen, Mads F. Hjorth, David B. Allison, Gary Taubes, Eric Ravussin, Mark I. Friedman, Kevin D. Hall, David S. Ludwig, John R. Speakman, Arne Astrup","doi":"10.1038/s42255-024-01106-8","DOIUrl":"10.1038/s42255-024-01106-8","url":null,"abstract":"Application of the physical laws of energy and mass conservation at the whole-body level is not necessarily informative about causal mechanisms of weight gain and the development of obesity. The energy balance model (EBM) and the carbohydrate–insulin model (CIM) are two plausible theories, among several others, attempting to explain why obesity develops within an overall common physiological framework of regulation of human energy metabolism. These models have been used to explain the pathogenesis of obesity in individuals as well as the dramatic increases in the prevalence of obesity worldwide over the past half century. Here, we summarize outcomes of a recent workshop in Copenhagen that brought together obesity experts from around the world to discuss causal models of obesity pathogenesis. These discussions helped to operationally define commonly used terms; delineate the structure of each model, particularly focussing on areas of overlap and divergence; challenge ideas about the importance of purported causal factors for weight gain; and brainstorm on the key scientific questions that need to be answered. We hope that more experimental research in nutrition and other related fields, and more testing of the models and their predictions will pave the way and provide more answers about the pathogenesis of obesity than those currently available. This authoritative Perspective lays a foundation for the field of obesity research by comparing commonalities and differences between competing models of obesity pathogenesis and by defining terms that are at the core of this discussion.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42255-024-01106-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142007535","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}
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