Nuclear receptors (NRs) regulate cellular processes and serve as key targets in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Their ability to interact and influence each other’s signaling pathways introduces a complex yet underexplored dimension in the pharmacotherapy of MASLD and MASH. This review delineates the emerging NRs in this field—estrogen-related receptor alpha (ERRα), glucocorticoid receptor (GR), estrogen receptor alpha (ERα), liver receptor homolog-1 (LRH-1), and vitamin D receptor (VDR)—and their interplay with established NRs, including peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, PPARγ), farnesoid X receptor (FXR), liver X receptors (LXR), hepatocyte nuclear factor 4α (HNF4α), and thyroid hormone receptor beta (THRβ). We discuss their collective impact on hepatic lipid metabolism, inflammation, fibrosis, and glucose homeostasis. We explore recent findings on dual NR crosstalk, via direct and indirect mechanisms, and discuss the potential of targeting receptor pathways using selective agonists, inverse agonists, antagonists, or specific modulators to combat MASLD and MASH. Elucidating NR interactions opens up new avenues for targeted therapies, emphasizing the critical need for further research in the evolving field of hepatology.
核受体（NR）调控细胞过程，是治疗代谢功能障碍相关性脂肪肝（MASLD）和脂肪性肝炎（MASH）的关键靶点。它们能够相互作用并影响彼此的信号通路，这为 MASLD 和 MASH 的药物治疗引入了一个复杂但尚未充分探索的维度。本综述描述了这一领域中新出现的 NRs--雌激素相关受体α（ERRα）、糖皮质激素受体（GR）、雌激素受体α（ERα）、肝脏受体同源物-1（LRH-1）和维生素 D 受体（VDR）--以及它们与已有 NRs 的相互作用、受体（PPARα、PPARβ/δ、PPARγ）、类雌激素 X 受体（FXR）、肝 X 受体（LXR）、肝细胞核因子 4α (HNF4α) 和甲状腺激素受体 beta (THRβ)。我们讨论了它们对肝脏脂质代谢、炎症、纤维化和糖稳态的共同影响。我们探讨了通过直接和间接机制进行双重 NR 相互影响的最新发现，并讨论了使用选择性激动剂、反向激动剂、拮抗剂或特异性调节剂靶向受体通路以对抗 MASLD 和 MASH 的可能性。阐明 NR 相互作用为靶向治疗开辟了新途径，强调了在不断发展的肝病学领域开展进一步研究的迫切需要。
{"title":"Unlocking therapeutic potential: exploring cross-talk among emerging nuclear receptors to combat metabolic dysfunction in steatotic liver disease","authors":"Milton Boaheng Antwi, Ariann Jennings, Sander Lefere, Dorien Clarisse, Anja Geerts, Lindsey Devisscher, Karolien De Bosscher","doi":"10.1038/s44324-024-00013-6","DOIUrl":"10.1038/s44324-024-00013-6","url":null,"abstract":"Nuclear receptors (NRs) regulate cellular processes and serve as key targets in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). Their ability to interact and influence each other’s signaling pathways introduces a complex yet underexplored dimension in the pharmacotherapy of MASLD and MASH. This review delineates the emerging NRs in this field—estrogen-related receptor alpha (ERRα), glucocorticoid receptor (GR), estrogen receptor alpha (ERα), liver receptor homolog-1 (LRH-1), and vitamin D receptor (VDR)—and their interplay with established NRs, including peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, PPARγ), farnesoid X receptor (FXR), liver X receptors (LXR), hepatocyte nuclear factor 4α (HNF4α), and thyroid hormone receptor beta (THRβ). We discuss their collective impact on hepatic lipid metabolism, inflammation, fibrosis, and glucose homeostasis. We explore recent findings on dual NR crosstalk, via direct and indirect mechanisms, and discuss the potential of targeting receptor pathways using selective agonists, inverse agonists, antagonists, or specific modulators to combat MASLD and MASH. Elucidating NR interactions opens up new avenues for targeted therapies, emphasizing the critical need for further research in the evolving field of hepatology.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00013-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141500494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s44324-024-00016-3
Annalise Schweickart, Richa Batra, Bryan J. Neth, Cameron Martino, Liat Shenhav, Anru R. Zhang, Pixu Shi, Naama Karu, Kevin Huynh, Peter J. Meikle, Leyla Schimmel, Amanda Hazel Dilmore, Kaj Blennow, Henrik Zetterberg, Colette Blach, Pieter C. Dorrestein, Rob Knight, Alzheimer’s Gut Microbiome Project Consortium, Suzanne Craft, Rima Kaddurah-Daouk, Jan Krumsiek
Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.
{"title":"Serum and CSF metabolomics analysis shows Mediterranean Ketogenic Diet mitigates risk factors of Alzheimer’s disease","authors":"Annalise Schweickart, Richa Batra, Bryan J. Neth, Cameron Martino, Liat Shenhav, Anru R. Zhang, Pixu Shi, Naama Karu, Kevin Huynh, Peter J. Meikle, Leyla Schimmel, Amanda Hazel Dilmore, Kaj Blennow, Henrik Zetterberg, Colette Blach, Pieter C. Dorrestein, Rob Knight, Alzheimer’s Gut Microbiome Project Consortium, Suzanne Craft, Rima Kaddurah-Daouk, Jan Krumsiek","doi":"10.1038/s44324-024-00016-3","DOIUrl":"10.1038/s44324-024-00016-3","url":null,"abstract":"Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00016-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s44324-024-00012-7
Sharen Lee, Tong Liu, Cheuk To Chung, Johannes Reinhold, Vassilios S. Vassiliou, Gary Tse
The aim of this study is to review the predictive value of visit-to-visit variability in glycaemic or lipid tests for forecasting major adverse cardiovascular events (MACE) in diabetes mellitus. Data from existing studies suggests that such variability is an independent predictor of adverse outcomes in this patient cohort. This understanding is then applied to the development of PowerAI-Diabetes, a Chinese-specific artificial intelligence-enhanced predictive model for predicting the risks of major adverse cardiovascular events and diabetic complications. The model integrates an amalgam of variables including demographics, laboratory and medication information to assess the risk of MACE. Future efforts should focus on the incorporation of treatment effects and non-traditional cardiovascular risk factors, such as social determinants of health variables, to improve the performance of predictive models.
{"title":"PowerAI-Diabetes: Review of glycemic and lipid variability to predict cardiovascular events in Chinese diabetic population","authors":"Sharen Lee, Tong Liu, Cheuk To Chung, Johannes Reinhold, Vassilios S. Vassiliou, Gary Tse","doi":"10.1038/s44324-024-00012-7","DOIUrl":"10.1038/s44324-024-00012-7","url":null,"abstract":"The aim of this study is to review the predictive value of visit-to-visit variability in glycaemic or lipid tests for forecasting major adverse cardiovascular events (MACE) in diabetes mellitus. Data from existing studies suggests that such variability is an independent predictor of adverse outcomes in this patient cohort. This understanding is then applied to the development of PowerAI-Diabetes, a Chinese-specific artificial intelligence-enhanced predictive model for predicting the risks of major adverse cardiovascular events and diabetic complications. The model integrates an amalgam of variables including demographics, laboratory and medication information to assess the risk of MACE. Future efforts should focus on the incorporation of treatment effects and non-traditional cardiovascular risk factors, such as social determinants of health variables, to improve the performance of predictive models.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-9"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00012-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s44324-024-00010-9
In Ah Choi, Akio Umemoto, Masataka Mizuno, Kyung-Hyun Park-Min
Bone is constantly being remodeled, and this process is orchestrated by a dynamic crosstalk of bone cells, including osteoclasts, osteoblasts, and osteocytes. Recent evidence suggests that cellular metabolism plays a crucial role in the differentiation and function of bone cells and facilitates the adaptation of bone cells to changes in the bone microenvironment. Moreover, bone affects whole-body energy metabolism. However, it is not yet completely understood how different cells in bone coordinate metabolic processes under physiological conditions, and how altered metabolic processes in bone cells contribute to pathological conditions where the balance among bone cells is disrupted. Therefore, gaining a better understanding of the distinct metabolic requirements of bone cells can provide crucial insights into the dysfunction of bone cells in pathological conditions and can be used to identify new therapeutic approaches to treat bone diseases. Here, we discuss recent advances in understanding metabolic reprogramming in bone cells.
{"title":"Bone metabolism – an underappreciated player","authors":"In Ah Choi, Akio Umemoto, Masataka Mizuno, Kyung-Hyun Park-Min","doi":"10.1038/s44324-024-00010-9","DOIUrl":"10.1038/s44324-024-00010-9","url":null,"abstract":"Bone is constantly being remodeled, and this process is orchestrated by a dynamic crosstalk of bone cells, including osteoclasts, osteoblasts, and osteocytes. Recent evidence suggests that cellular metabolism plays a crucial role in the differentiation and function of bone cells and facilitates the adaptation of bone cells to changes in the bone microenvironment. Moreover, bone affects whole-body energy metabolism. However, it is not yet completely understood how different cells in bone coordinate metabolic processes under physiological conditions, and how altered metabolic processes in bone cells contribute to pathological conditions where the balance among bone cells is disrupted. Therefore, gaining a better understanding of the distinct metabolic requirements of bone cells can provide crucial insights into the dysfunction of bone cells in pathological conditions and can be used to identify new therapeutic approaches to treat bone diseases. Here, we discuss recent advances in understanding metabolic reprogramming in bone cells.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-10"},"PeriodicalIF":0.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00010-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141489069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paternal eating habits, before and at conception, have a strong impact on offspring future metabolism. By sending specific epigenetic signals through spermatozoa, paternal nutrition influences developing embryos and increases offspring risk of developing dysmetabolism and cardiovascular diseases. Among the intergenerational consequences, paternal epigenetic messages affect embryo DNA methylation altering programmed gene expression. The identification of offspring genetic loci that are epigenetically altered by paternal stimuli is of pivotal interest for timely post-natal treatment of offspring metabolic defects. We here use a murine model to show that, cyp19a1/aromatase, a gene coding for the cytochrome converting testosterone into 17-β estradiol (both potent hormonal mediators of embryo development and metabolism), is an epigenetic transducer of paternal intergenerational inheritance. By affecting cyp19a1 methylation status and alternative splicing, paternal diet coordinates androgens’ metabolism in the progeny affecting it in a sexually dimorphic way and promoting hypoandrogenism, growth retardation and diabetes in male pups.
父亲在受孕前和受孕时的饮食习惯对后代未来的新陈代谢有很大影响。父亲的营养通过精子发出特定的表观遗传信号，影响发育中的胚胎，增加后代患代谢紊乱和心血管疾病的风险。在代际后果中，父亲的表观遗传信息会影响胚胎的 DNA 甲基化，改变程序基因的表达。确定受父代刺激而发生表观遗传改变的子代基因位点，对及时治疗子代代谢缺陷具有重要意义。我们在此利用小鼠模型证明，cyp19a1/aromatase（一种编码将睾酮转化为 17-β 雌二醇（两者都是胚胎发育和代谢的强效激素介质）的细胞色素的基因）是父系代际遗传的表观遗传转换器。通过影响 cyp19a1 的甲基化状态和替代剪接，父亲的饮食会协调后代的雄性激素代谢，以性别二态的方式影响后代，并促进雄性幼崽的雄性激素过低、生长迟缓和糖尿病。
{"title":"Pre-conceptional paternal diet impacts on offspring testosterone homoeostasis via epigenetic modulation of cyp19a1/aromatase activity","authors":"Arianna Pastore, Nadia Badolati, Francesco Manfrevola, Serena Sagliocchi, Valentina Laurenzi, Giorgia Musto, Veronica Porreca, Melania Murolo, Teresa Chioccarelli, Roberto Ciampaglia, Valentina Vellecco, Mariarosaria Bucci, Monica Dentice, Gilda Cobellis, Mariano Stornaiuolo","doi":"10.1038/s44324-024-00011-8","DOIUrl":"10.1038/s44324-024-00011-8","url":null,"abstract":"Paternal eating habits, before and at conception, have a strong impact on offspring future metabolism. By sending specific epigenetic signals through spermatozoa, paternal nutrition influences developing embryos and increases offspring risk of developing dysmetabolism and cardiovascular diseases. Among the intergenerational consequences, paternal epigenetic messages affect embryo DNA methylation altering programmed gene expression. The identification of offspring genetic loci that are epigenetically altered by paternal stimuli is of pivotal interest for timely post-natal treatment of offspring metabolic defects. We here use a murine model to show that, cyp19a1/aromatase, a gene coding for the cytochrome converting testosterone into 17-β estradiol (both potent hormonal mediators of embryo development and metabolism), is an epigenetic transducer of paternal intergenerational inheritance. By affecting cyp19a1 methylation status and alternative splicing, paternal diet coordinates androgens’ metabolism in the progeny affecting it in a sexually dimorphic way and promoting hypoandrogenism, growth retardation and diabetes in male pups.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-14"},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00011-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-03DOI: 10.1038/s44324-024-00009-2
Pialuisa Quiriconi, Vanco Hristov, Mayu Aburaya, Una Greferath, Andrew I. Jobling, Erica L. Fletcher
Diabetic retinopathy is a vision-threatening disease and remains the most feared complication for those living with diabetes. Historically, the disease has been considered primarily vascular in nature, based on clinically detectable vascular pathology. Nonetheless, it is now recognized that the retina undergoes a variety of cellular changes from the early onset of diabetes. In fact, one of the earliest changes to occur is a loss in vasoregulation, yet our understanding of the underlying mechanisms is lacking. Microglia, the resident immune cells of the central nervous system, perform a range of physiological, non-inflammatory functions to maintain retinal homeostasis which includes surveying the microenvironment to constantly monitor tissue health, neuronal surveillance to maintain synaptic integrity and vasoregulation, a recently discovered role that these cells additionally perform. The role of microglia in the development of diabetic retinopathy is well-established, centered around their contribution to inflammation which remains an integral component in disease pathogenesis, particularly in later stages of disease. However, recent findings reveal that early in the development of diabetes the vasoregulatory function of microglia is dysfunctional, leading to early vascular compromise. This review summarizes recent work to highlight how microglia are affected by diabetes and the implications of these changes in the development of diabetic retinopathy from pre-clinical to advanced stages of disease.
{"title":"The role of microglia in the development of diabetic retinopathy","authors":"Pialuisa Quiriconi, Vanco Hristov, Mayu Aburaya, Una Greferath, Andrew I. Jobling, Erica L. Fletcher","doi":"10.1038/s44324-024-00009-2","DOIUrl":"10.1038/s44324-024-00009-2","url":null,"abstract":"Diabetic retinopathy is a vision-threatening disease and remains the most feared complication for those living with diabetes. Historically, the disease has been considered primarily vascular in nature, based on clinically detectable vascular pathology. Nonetheless, it is now recognized that the retina undergoes a variety of cellular changes from the early onset of diabetes. In fact, one of the earliest changes to occur is a loss in vasoregulation, yet our understanding of the underlying mechanisms is lacking. Microglia, the resident immune cells of the central nervous system, perform a range of physiological, non-inflammatory functions to maintain retinal homeostasis which includes surveying the microenvironment to constantly monitor tissue health, neuronal surveillance to maintain synaptic integrity and vasoregulation, a recently discovered role that these cells additionally perform. The role of microglia in the development of diabetic retinopathy is well-established, centered around their contribution to inflammation which remains an integral component in disease pathogenesis, particularly in later stages of disease. However, recent findings reveal that early in the development of diabetes the vasoregulatory function of microglia is dysfunctional, leading to early vascular compromise. This review summarizes recent work to highlight how microglia are affected by diabetes and the implications of these changes in the development of diabetic retinopathy from pre-clinical to advanced stages of disease.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00009-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141246193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-27DOI: 10.1038/s44324-024-00008-3
Eloïse Marques, Robbin Kramer, Dylan G. Ryan
The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.
{"title":"Multifaceted mitochondria in innate immunity","authors":"Eloïse Marques, Robbin Kramer, Dylan G. Ryan","doi":"10.1038/s44324-024-00008-3","DOIUrl":"10.1038/s44324-024-00008-3","url":null,"abstract":"The ability of mitochondria to transform the energy we obtain from food into cell phosphorylation potential has long been appreciated. However, recent decades have seen an evolution in our understanding of mitochondria, highlighting their significance as key signal-transducing organelles with essential roles in immunity that extend beyond their bioenergetic function. Importantly, mitochondria retain bacterial motifs as a remnant of their endosymbiotic origin that are recognised by innate immune cells to trigger inflammation and participate in anti-microbial defence. This review aims to explore how mitochondrial physiology, spanning from oxidative phosphorylation (OxPhos) to signalling of mitochondrial nucleic acids, metabolites, and lipids, influences the effector functions of phagocytes. These myriad effector functions include macrophage polarisation, efferocytosis, anti-bactericidal activity, antigen presentation, immune signalling, and cytokine regulation. Strict regulation of these processes is critical for organismal homeostasis that when disrupted may cause injury or contribute to disease. Thus, the expanding body of literature, which continues to highlight the central role of mitochondria in the innate immune system, may provide insights for the development of the next generation of therapies for inflammatory diseases.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-15"},"PeriodicalIF":0.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00008-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-23DOI: 10.1038/s44324-024-00007-4
Logan V. Vick, Spencer Rosario, Jonathan W. Riess, Robert J. Canter, Sarbajit Mukherjee, Arta M. Monjazeb, William J. Murphy
Obesity, a condition of excess adiposity usually defined by a BMI > 30, can have profound effects on both metabolism and immunity, connecting the condition with a broad range of diseases, including cancer and negative outcomes. Obesity and cancer have been associated with increased incidence, progression, and poorer outcomes of multiple cancer types in part due to the pro-inflammatory state that arises. Surprisingly, obesity has also recently been demonstrated in both preclinical models and clinical outcomes to be associated with improved response to immune checkpoint inhibition (ICI). These observations have laid the foundation for what has been termed the “obesity paradox”. The mechanisms underlying these augmented immunotherapy responses are still unclear given the pleiotropic effects obesity exerts on cells and tissues. Other important variables such as age and sex are being examined as further affecting the obesity effect. Sex-linked factors exert significant influences on obesity biology, metabolism as well as differential effects of different immune cell-types. Age can be another confounding factor contributing to the effects on both sex-linked changes, immune status, and obesity. This review aims to revisit the current body of literature describing the immune and metabolic changes mediated by obesity, the role of obesity on cancer immunotherapy, and to highlight questions on how sex-linked differences may influence obesity and immunotherapy outcome.
{"title":"Potential roles of sex-linked differences in obesity and cancer immunotherapy: revisiting the obesity paradox","authors":"Logan V. Vick, Spencer Rosario, Jonathan W. Riess, Robert J. Canter, Sarbajit Mukherjee, Arta M. Monjazeb, William J. Murphy","doi":"10.1038/s44324-024-00007-4","DOIUrl":"10.1038/s44324-024-00007-4","url":null,"abstract":"Obesity, a condition of excess adiposity usually defined by a BMI > 30, can have profound effects on both metabolism and immunity, connecting the condition with a broad range of diseases, including cancer and negative outcomes. Obesity and cancer have been associated with increased incidence, progression, and poorer outcomes of multiple cancer types in part due to the pro-inflammatory state that arises. Surprisingly, obesity has also recently been demonstrated in both preclinical models and clinical outcomes to be associated with improved response to immune checkpoint inhibition (ICI). These observations have laid the foundation for what has been termed the “obesity paradox”. The mechanisms underlying these augmented immunotherapy responses are still unclear given the pleiotropic effects obesity exerts on cells and tissues. Other important variables such as age and sex are being examined as further affecting the obesity effect. Sex-linked factors exert significant influences on obesity biology, metabolism as well as differential effects of different immune cell-types. Age can be another confounding factor contributing to the effects on both sex-linked changes, immune status, and obesity. This review aims to revisit the current body of literature describing the immune and metabolic changes mediated by obesity, the role of obesity on cancer immunotherapy, and to highlight questions on how sex-linked differences may influence obesity and immunotherapy outcome.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00007-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141085135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-06DOI: 10.1038/s44324-024-00006-5
Angela S. Bruzina, Christiana J. Raymond-Pope, Kevin J. Murray, Thomas J. Lillquist, Katelyn M. Castelli, Shefali R. Bijwadia, Jarrod A. Call, Sarah M. Greising
Following traumatic musculoskeletal injuries, prolonged bedrest and loss of physical activity may limit muscle plasticity and drive metabolic dysfunction. One specific injury, volumetric muscle loss (VML), results in frank loss of muscle and is characterized by whole-body and cellular metabolic dysfunction. However, how VML and restricted physical activity limit plasticity of the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle remains unclear. Adult mice were randomized to posterior hindlimb compartment VML or were age-matched injury naïve controls, then randomized to standard or restricted activity cages for 8-wks. Activity restriction in naïve mice resulted in ~5% greater respiratory exchange ratio (RER); combined with VML, carbohydrate oxidation was ~23% greater than VML alone, but lipid oxidation was largely unchanged. Activity restriction combined with VML increased whole-body carbohydrate usage. Together there was a greater pACC:ACC ratio in the muscle remaining, which may contribute to decreased fatty acid synthesis. Further, β-HAD activity normalized to mitochondrial content was decreased following VML, suggesting a diminished capacity to oxidize fatty acids. The muscle metabolome was not altered by the restriction of physical activity. The combination of VML and activity restriction resulted in similar ( ~ 91%) up- and down-regulated metabolites and/or ratios, suggesting that VML injury alone is regulating changes in the metabolome. Data supports possible VML-induced alterations in fatty acid metabolism are exacerbated by activity restriction. Collectively, this work adds to the sequalae of VML injury, exhausting the ability of the muscle remaining to oxidize fatty acids resulting in a possible accumulation of triglycerides.
{"title":"Limitations in metabolic plasticity after traumatic injury are only moderately exacerbated by physical activity restriction","authors":"Angela S. Bruzina, Christiana J. Raymond-Pope, Kevin J. Murray, Thomas J. Lillquist, Katelyn M. Castelli, Shefali R. Bijwadia, Jarrod A. Call, Sarah M. Greising","doi":"10.1038/s44324-024-00006-5","DOIUrl":"10.1038/s44324-024-00006-5","url":null,"abstract":"Following traumatic musculoskeletal injuries, prolonged bedrest and loss of physical activity may limit muscle plasticity and drive metabolic dysfunction. One specific injury, volumetric muscle loss (VML), results in frank loss of muscle and is characterized by whole-body and cellular metabolic dysfunction. However, how VML and restricted physical activity limit plasticity of the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle remains unclear. Adult mice were randomized to posterior hindlimb compartment VML or were age-matched injury naïve controls, then randomized to standard or restricted activity cages for 8-wks. Activity restriction in naïve mice resulted in ~5% greater respiratory exchange ratio (RER); combined with VML, carbohydrate oxidation was ~23% greater than VML alone, but lipid oxidation was largely unchanged. Activity restriction combined with VML increased whole-body carbohydrate usage. Together there was a greater pACC:ACC ratio in the muscle remaining, which may contribute to decreased fatty acid synthesis. Further, β-HAD activity normalized to mitochondrial content was decreased following VML, suggesting a diminished capacity to oxidize fatty acids. The muscle metabolome was not altered by the restriction of physical activity. The combination of VML and activity restriction resulted in similar ( ~ 91%) up- and down-regulated metabolites and/or ratios, suggesting that VML injury alone is regulating changes in the metabolome. Data supports possible VML-induced alterations in fatty acid metabolism are exacerbated by activity restriction. Collectively, this work adds to the sequalae of VML injury, exhausting the ability of the muscle remaining to oxidize fatty acids resulting in a possible accumulation of triglycerides.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00006-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140351741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-15DOI: 10.1038/s44324-024-00005-6
Natalia Pardo-Lorente, Sara Sdelci
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme of the folate-mediated one-carbon metabolism pathway. MTHFD2 has become a highly attractive therapeutic target due to its consistent upregulation in cancer tissues and its major contribution to tumor progression, although it also performs vital functions in proliferating healthy cells. Here, we review the diversity of canonical and non-canonical functions of this key metabolic enzyme under physiological conditions and in carcinogenesis. We provide an overview of its therapeutic potential and describe its regulatory mechanisms. In addition, we discuss the recently described non-canonical functions of MTHFD2 and the mechanistic basis of its oncogenic function. Finally, we speculate on novel therapeutic approaches that take into account subcellular compartmentalization and outline new research directions that would contribute to a better understanding of the fundamental roles of this metabolic enzyme in health and disease.
{"title":"MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions","authors":"Natalia Pardo-Lorente, Sara Sdelci","doi":"10.1038/s44324-024-00005-6","DOIUrl":"10.1038/s44324-024-00005-6","url":null,"abstract":"Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme of the folate-mediated one-carbon metabolism pathway. MTHFD2 has become a highly attractive therapeutic target due to its consistent upregulation in cancer tissues and its major contribution to tumor progression, although it also performs vital functions in proliferating healthy cells. Here, we review the diversity of canonical and non-canonical functions of this key metabolic enzyme under physiological conditions and in carcinogenesis. We provide an overview of its therapeutic potential and describe its regulatory mechanisms. In addition, we discuss the recently described non-canonical functions of MTHFD2 and the mechanistic basis of its oncogenic function. Finally, we speculate on novel therapeutic approaches that take into account subcellular compartmentalization and outline new research directions that would contribute to a better understanding of the fundamental roles of this metabolic enzyme in health and disease.","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":" ","pages":"1-12"},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s44324-024-00005-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140135485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：