Pub Date : 2023-11-07Epub Date: 2023-10-18DOI: 10.1016/j.cmet.2023.09.013
Dongxiang Xue, Narisu Narisu, D Leland Taylor, Meili Zhang, Caleb Grenko, Henry J Taylor, Tingfen Yan, Xuming Tang, Neelam Sinha, Jiajun Zhu, J Jeya Vandana, Angie Chi Nok Chong, Angela Lee, Erin C Mansell, Amy J Swift, Michael R Erdos, Aaron Zhong, Lori L Bonnycastle, Ting Zhou, Shuibing Chen, Francis S Collins
Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.
{"title":"Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells.","authors":"Dongxiang Xue, Narisu Narisu, D Leland Taylor, Meili Zhang, Caleb Grenko, Henry J Taylor, Tingfen Yan, Xuming Tang, Neelam Sinha, Jiajun Zhu, J Jeya Vandana, Angie Chi Nok Chong, Angela Lee, Erin C Mansell, Amy J Swift, Michael R Erdos, Aaron Zhong, Lori L Bonnycastle, Ting Zhou, Shuibing Chen, Francis S Collins","doi":"10.1016/j.cmet.2023.09.013","DOIUrl":"10.1016/j.cmet.2023.09.013","url":null,"abstract":"<p><p>Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":" ","pages":"1897-1914.e11"},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49686265","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 : 2023-11-07DOI: 10.1016/j.cmet.2023.10.005
Cara L Green, Michaela E Trautman, Krittisak Chaiyakul, Raghav Jain, Yasmine H Alam, Reji Babygirija, Heidi H Pak, Michelle M Sonsalla, Mariah F Calubag, Chung-Yang Yeh, Anneliese Bleicher, Grace Novak, Teresa T Liu, Sarah Newman, Will A Ricke, Kristina A Matkowskyj, Irene M Ong, Cholsoon Jang, Judith Simcox, Dudley W Lamming
Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.
{"title":"Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.","authors":"Cara L Green, Michaela E Trautman, Krittisak Chaiyakul, Raghav Jain, Yasmine H Alam, Reji Babygirija, Heidi H Pak, Michelle M Sonsalla, Mariah F Calubag, Chung-Yang Yeh, Anneliese Bleicher, Grace Novak, Teresa T Liu, Sarah Newman, Will A Ricke, Kristina A Matkowskyj, Irene M Ong, Cholsoon Jang, Judith Simcox, Dudley W Lamming","doi":"10.1016/j.cmet.2023.10.005","DOIUrl":"10.1016/j.cmet.2023.10.005","url":null,"abstract":"<p><p>Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"35 11","pages":"1976-1995.e6"},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10655617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71523771","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}
Overeating disorders (ODs), usually stemming from dieting history and stress, remain a pervasive issue in contemporary society, with the pathological mechanisms largely unresolved. Here, we show that alterations in intestinal microbiota are responsible for the excessive intake of palatable foods in OD mice and patients with bulimia nervosa (BN). Stress combined with a history of dieting causes significant changes in the microbiota and the intestinal metabolism, which disinhibit the vagus nerve terminals in the gut and thereby lead to a subsequent hyperactivation of the gut-brain axis passing through the vagus, the solitary tract nucleus, and the paraventricular nucleus of the thalamus. The transplantation of a probiotic Faecalibacterium prausnitzii or dietary supplement of key metabolites restores the activity of the gut-to-brain pathway and thereby alleviates the OD symptoms. Thus, our study delineates how the microbiota-gut-brain axis mediates energy balance, unveils the underlying pathogenesis of the OD, and provides potential therapeutic strategies.
{"title":"Microbiota-gut-brain axis drives overeating disorders.","authors":"Sijia Fan, Weiwei Guo, Dan Xiao, Mengyuan Guan, Tiepeng Liao, Sufang Peng, Airong Feng, Ziyi Wang, Hao Yin, Min Li, Jue Chen, Wei Xiong","doi":"10.1016/j.cmet.2023.09.005","DOIUrl":"10.1016/j.cmet.2023.09.005","url":null,"abstract":"<p><p>Overeating disorders (ODs), usually stemming from dieting history and stress, remain a pervasive issue in contemporary society, with the pathological mechanisms largely unresolved. Here, we show that alterations in intestinal microbiota are responsible for the excessive intake of palatable foods in OD mice and patients with bulimia nervosa (BN). Stress combined with a history of dieting causes significant changes in the microbiota and the intestinal metabolism, which disinhibit the vagus nerve terminals in the gut and thereby lead to a subsequent hyperactivation of the gut-brain axis passing through the vagus, the solitary tract nucleus, and the paraventricular nucleus of the thalamus. The transplantation of a probiotic Faecalibacterium prausnitzii or dietary supplement of key metabolites restores the activity of the gut-to-brain pathway and thereby alleviates the OD symptoms. Thus, our study delineates how the microbiota-gut-brain axis mediates energy balance, unveils the underlying pathogenesis of the OD, and provides potential therapeutic strategies.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":" ","pages":"2011-2027.e7"},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41175350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-07DOI: 10.1016/j.cmet.2023.10.011
Yu-Wei Cheng, Jie Liu, Toren Finkel
Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.
{"title":"Mitohormesis.","authors":"Yu-Wei Cheng, Jie Liu, Toren Finkel","doi":"10.1016/j.cmet.2023.10.011","DOIUrl":"10.1016/j.cmet.2023.10.011","url":null,"abstract":"<p><p>Perturbation of mitochondrial function can trigger a host of cellular responses that seek to restore cellular metabolism, cytosolic proteostasis, and redox homeostasis. In some cases, these responses persist even after the stress is relieved, leaving the cell or tissue in a less vulnerable state. This process-termed mitohormesis-is increasingly viewed as an important aspect of normal physiology and a critical modulator of various disease processes. Here, we review aspects of mitochondrial stress signaling that, among other things, can rewire the cell's metabolism, activate the integrated stress response, and alter cytosolic quality-control pathways. We also discuss how these pathways are implicated in various disease states from pathogen challenge to chemotherapeutic resistance and how their therapeutic manipulation can lead to new strategies for a host of chronic conditions including aging itself.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"35 11","pages":"1872-1886"},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71523773","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 : 2023-11-07Epub Date: 2023-10-27DOI: 10.1016/j.cmet.2023.10.001
Mayur Doke, Silvia Álvarez-Cubela, Dagmar Klein, Isabella Altilio, Joseph Schulz, Luciana Mateus Gonçalves, Joana Almaça, Christopher A Fraker, Alberto Pugliese, Camillo Ricordi, Mirza M F Qadir, Ricardo L Pastori, Juan Domínguez-Bendala
Human pancreatic plasticity is implied from multiple single-cell RNA sequencing (scRNA-seq) studies. However, these have been invariably based on static datasets from which fate trajectories can only be inferred using pseudotemporal estimations. Furthermore, the analysis of isolated islets has resulted in a drastic underrepresentation of other cell types, hindering our ability to interrogate exocrine-endocrine interactions. The long-term culture of human pancreatic slices (HPSs) has presented the field with an opportunity to dynamically track tissue plasticity at the single-cell level. Combining datasets from same-donor HPSs at different time points, with or without a known regenerative stimulus (BMP signaling), led to integrated single-cell datasets storing true temporal or treatment-dependent information. This integration revealed population shifts consistent with ductal progenitor activation, blurring of ductal/acinar boundaries, formation of ducto-acinar-endocrine differentiation axes, and detection of transitional insulin-producing cells. This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion.
{"title":"Dynamic scRNA-seq of live human pancreatic slices reveals functional endocrine cell neogenesis through an intermediate ducto-acinar stage.","authors":"Mayur Doke, Silvia Álvarez-Cubela, Dagmar Klein, Isabella Altilio, Joseph Schulz, Luciana Mateus Gonçalves, Joana Almaça, Christopher A Fraker, Alberto Pugliese, Camillo Ricordi, Mirza M F Qadir, Ricardo L Pastori, Juan Domínguez-Bendala","doi":"10.1016/j.cmet.2023.10.001","DOIUrl":"10.1016/j.cmet.2023.10.001","url":null,"abstract":"<p><p>Human pancreatic plasticity is implied from multiple single-cell RNA sequencing (scRNA-seq) studies. However, these have been invariably based on static datasets from which fate trajectories can only be inferred using pseudotemporal estimations. Furthermore, the analysis of isolated islets has resulted in a drastic underrepresentation of other cell types, hindering our ability to interrogate exocrine-endocrine interactions. The long-term culture of human pancreatic slices (HPSs) has presented the field with an opportunity to dynamically track tissue plasticity at the single-cell level. Combining datasets from same-donor HPSs at different time points, with or without a known regenerative stimulus (BMP signaling), led to integrated single-cell datasets storing true temporal or treatment-dependent information. This integration revealed population shifts consistent with ductal progenitor activation, blurring of ductal/acinar boundaries, formation of ducto-acinar-endocrine differentiation axes, and detection of transitional insulin-producing cells. This study provides the first longitudinal scRNA-seq analysis of whole human pancreatic tissue, confirming its plasticity in a dynamic fashion.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":" ","pages":"1944-1960.e7"},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66784769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-03DOI: 10.1016/j.cmet.2023.09.003
Ryan Wallis, Cleo L Bishop
Killing senescent cells to improve health-span holds great promise. However, screening for senescence-regulating genes and molecules is challenging because these cells do not proliferate. In this issue, Colville and Liu et al. develop Death-seq, a positive selection screening tool that overcomes this hurdle to offer broad genetic and pharmacological utility.
{"title":"Death-seq and ye shall find: A novel screening strategy for dying cells.","authors":"Ryan Wallis, Cleo L Bishop","doi":"10.1016/j.cmet.2023.09.003","DOIUrl":"10.1016/j.cmet.2023.09.003","url":null,"abstract":"<p><p>Killing senescent cells to improve health-span holds great promise. However, screening for senescence-regulating genes and molecules is challenging because these cells do not proliferate. In this issue, Colville and Liu et al. develop Death-seq, a positive selection screening tool that overcomes this hurdle to offer broad genetic and pharmacological utility.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"35 10","pages":"1675-1676"},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41165103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-03DOI: 10.1016/j.cmet.2023.09.004
Yun Zhao, Zhongshun Liu, Guoqiang Liu, Yuting Zhang, Sheng Liu, Dailin Gan, Wennan Chang, Xiaoxia Peng, Eun Suh Sung, Keegan Gilbert, Yini Zhu, Xuechun Wang, Ziyu Zeng, Hope Baldwin, Guanzhu Ren, Jessica Weaver, Anna Huron, Toni Mayberry, Qingfei Wang, Yujue Wang, Maria Elena Diaz-Rubio, Xiaoyang Su, M Sharon Stack, Siyuan Zhang, Xuemin Lu, Ryan D Sheldon, Jun Li, Chi Zhang, Jun Wan, Xin Lu
Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.
{"title":"Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1.","authors":"Yun Zhao, Zhongshun Liu, Guoqiang Liu, Yuting Zhang, Sheng Liu, Dailin Gan, Wennan Chang, Xiaoxia Peng, Eun Suh Sung, Keegan Gilbert, Yini Zhu, Xuechun Wang, Ziyu Zeng, Hope Baldwin, Guanzhu Ren, Jessica Weaver, Anna Huron, Toni Mayberry, Qingfei Wang, Yujue Wang, Maria Elena Diaz-Rubio, Xiaoyang Su, M Sharon Stack, Siyuan Zhang, Xuemin Lu, Ryan D Sheldon, Jun Li, Chi Zhang, Jun Wan, Xin Lu","doi":"10.1016/j.cmet.2023.09.004","DOIUrl":"10.1016/j.cmet.2023.09.004","url":null,"abstract":"<p><p>Metastasis causes breast cancer-related mortality. Tumor-infiltrating neutrophils (TINs) inflict immunosuppression and promote metastasis. Therapeutic debilitation of TINs may enhance immunotherapy, yet it remains a challenge to identify therapeutic targets highly expressed and functionally essential in TINs but under-expressed in extra-tumoral neutrophils. Here, using single-cell RNA sequencing to compare TINs and circulating neutrophils in murine mammary tumor models, we identified aconitate decarboxylase 1 (Acod1) as the most upregulated metabolic enzyme in mouse TINs and validated high Acod1 expression in human TINs. Activated through the GM-CSF-JAK/STAT5-C/EBPβ pathway, Acod1 produces itaconate, which mediates Nrf2-dependent defense against ferroptosis and upholds the persistence of TINs. Acod1 ablation abates TIN infiltration, constrains metastasis (but not primary tumors), bolsters antitumor T cell immunity, and boosts the efficacy of immune checkpoint blockade. Our findings reveal how TINs escape from ferroptosis through the Acod1-dependent immunometabolism switch and establish Acod1 as a target to offset immunosuppression and improve immunotherapy against metastasis.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"35 10","pages":"1688-1703.e10"},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41168529","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 : 2023-10-03DOI: 10.1016/j.cmet.2023.09.006
Xiao Tian, David A Sinclair
Alzheimer's disease is often accompanied by disruptions in circadian rhythms, which may exacerbate the disease's progression. In this issue, Whittaker and colleagues demonstrate that the modulation of circadian rhythms by time-restricted feeding can alter the disease trajectory in Alzheimer's mouse models.
{"title":"Restricting mealtime ameliorates neurodegeneration.","authors":"Xiao Tian, David A Sinclair","doi":"10.1016/j.cmet.2023.09.006","DOIUrl":"10.1016/j.cmet.2023.09.006","url":null,"abstract":"<p><p>Alzheimer's disease is often accompanied by disruptions in circadian rhythms, which may exacerbate the disease's progression. In this issue, Whittaker and colleagues demonstrate that the modulation of circadian rhythms by time-restricted feeding can alter the disease trajectory in Alzheimer's mouse models.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"35 10","pages":"1673-1674"},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41179897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-10-03Epub Date: 2023-09-20DOI: 10.1016/j.cmet.2023.08.010
Maike Becker, Sini S Joseph, Francisco Garcia-Carrizo, Robby Z Tom, Daria Opaleva, Isabelle Serr, Matthias H Tschöp, Tim J Schulz, Susanna M Hofmann, Carolin Daniel
Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.
{"title":"Regulatory T cells require IL6 receptor alpha signaling to control skeletal muscle function and regeneration.","authors":"Maike Becker, Sini S Joseph, Francisco Garcia-Carrizo, Robby Z Tom, Daria Opaleva, Isabelle Serr, Matthias H Tschöp, Tim J Schulz, Susanna M Hofmann, Carolin Daniel","doi":"10.1016/j.cmet.2023.08.010","DOIUrl":"10.1016/j.cmet.2023.08.010","url":null,"abstract":"<p><p>Muscle-residing regulatory T cells (Tregs) control local tissue integrity and function. However, the molecular interface connecting Treg-based regulation with muscle function and regeneration remains largely unexplored. Here, we show that exercise fosters a stable induction of highly functional muscle-residing Tregs with increased expression of amphiregulin (Areg), EGFR, and ST2. Mechanistically, we find that mice lacking IL6Rα on T cells (TKO) harbor significant reductions in muscle Treg functionality and satellite and fibro-adipogenic progenitor cells, which are required for muscle regeneration. Using exercise and sarcopenia models, IL6Rα TKO mice demonstrate deficits in Tregs, their functional maturation, and a more pronounced decline in muscle mass. Muscle injury models indicate that IL6Rα TKO mice have significant disabilities in muscle regeneration. Treg gain of function restores impaired muscle repair in IL6Rα TKO mice. Of note, pharmacological IL6R blockade in WT mice phenocopies deficits in muscle function identified in IL6Rα TKO mice, thereby highlighting the clinical implications of the findings.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"35 10","pages":"1736-1751.e7"},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10563138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157431","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 : 2023-10-03DOI: 10.1016/j.cmet.2023.09.001
Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme
Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.
{"title":"Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.","authors":"Kira L Tomlinson, Ying-Tsun Chen, Alex Junker, AndreaCarola Urso, Tania Wong Fok Lung, Danielle Ahn, Casey E Hofstaedter, Swikrity U Baskota, Robert K Ernst, Alice Prince, Sebastián A Riquelme","doi":"10.1016/j.cmet.2023.09.001","DOIUrl":"10.1016/j.cmet.2023.09.001","url":null,"abstract":"<p><p>Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.</p>","PeriodicalId":93927,"journal":{"name":"Cell metabolism","volume":"35 10","pages":"1767-1781.e6"},"PeriodicalIF":0.0,"publicationDate":"2023-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10558090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41158151","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}