Pub Date : 2024-08-13DOI: 10.1038/s42255-024-01109-5
Fenglei Wang, Andrea J. Glenn, Anne-Julie Tessier, Zhendong Mei, Danielle E. Haslam, Marta Guasch-Ferré, Deirdre K. Tobias, A. Heather Eliassen, JoAnn E. Manson, Clary Clish, Kyu Ha Lee, Eric B. Rimm, Dong D. Wang, Qi Sun, Liming Liang, Walter C. Willett, Frank B. Hu
Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20–1.33; P for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including l-valine and uric acid, potentially mediating the haem iron–T2D relationship, highlighting their pivotal role in T2D pathogenesis.
{"title":"Integration of epidemiological and blood biomarker analysis links haem iron intake to increased type 2 diabetes risk","authors":"Fenglei Wang, Andrea J. Glenn, Anne-Julie Tessier, Zhendong Mei, Danielle E. Haslam, Marta Guasch-Ferré, Deirdre K. Tobias, A. Heather Eliassen, JoAnn E. Manson, Clary Clish, Kyu Ha Lee, Eric B. Rimm, Dong D. Wang, Qi Sun, Liming Liang, Walter C. Willett, Frank B. Hu","doi":"10.1038/s42255-024-01109-5","DOIUrl":"https://doi.org/10.1038/s42255-024-01109-5","url":null,"abstract":"<p>Dietary haem iron intake is linked to an increased risk of type 2 diabetes (T2D), but the underlying plasma biomarkers are not well understood. We analysed data from 204,615 participants (79% females) in three large US cohorts over up to 36 years, examining the associations between iron intake and T2D risk. We also assessed plasma metabolic biomarkers and metabolomic profiles in subsets of 37,544 (82% females) and 9,024 (84% females) participants, respectively. Here we show that haem iron intake but not non-haem iron is associated with a higher T2D risk, with a multivariable-adjusted hazard ratio of 1.26 (95% confidence interval 1.20–1.33; <i>P</i> for trend <0.001) comparing the highest to the lowest quintiles. Haem iron accounts for significant proportions of the T2D risk linked to unprocessed red meat and specific dietary patterns. Increased haem iron intake correlates with unfavourable plasma profiles of insulinaemia, lipids, inflammation and T2D-linked metabolites. We also identify metabolites, including <span>l</span>-valine and uric acid, potentially mediating the haem iron–T2D relationship, highlighting their pivotal role in T2D pathogenesis.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":20.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141973772","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 : 2024-08-12DOI: 10.1038/s42255-024-01093-w
Junhong Qin, Xinhe Huang, Shengsong Gou, Sitao Zhang, Yujie Gou, Qian Zhang, Hongyu Chen, Lin Sun, Miaomiao Chen, Dan Liu, Cheng Han, Min Tang, Zihao Feng, Shenghui Niu, Lin Zhao, Yingfeng Tu, Zexian Liu, Weimin Xuan, Lunzhi Dai, Da Jia, Yu Xue
Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification induced by the ketogenic diet (KD), a diet showing therapeutic effects on multiple human diseases. Little is known how cellular processes are regulated by Kbhb. Here we show that protein Kbhb is strongly affected by the KD through a multi-omics analysis of mouse livers. Using a small training dataset with known functions, we developed a bioinformatics method for the prediction of functionally important lysine modification sites (pFunK), which revealed functionally relevant Kbhb sites on various proteins, including aldolase B (ALDOB) Lys108. KD consumption or β-hydroxybutyrate supplementation in hepatocellular carcinoma cells increases ALDOB Lys108bhb and inhibits the enzymatic activity of ALDOB. A Kbhb-mimicking mutation (p.Lys108Gln) attenuates ALDOB activity and its binding to substrate fructose-1,6-bisphosphate, inhibits mammalian target of rapamycin signalling and glycolysis, and markedly suppresses cancer cell proliferation. Our study reveals a critical role of Kbhb in regulating cancer cell metabolism and provides a generally applicable algorithm for predicting functionally important lysine modification sites. Multi-omics analysis of mouse livers shows that protein β-hydroxybutyrylation (Kbhb) is strongly affected by the ketogenic diet. Combining bioinformatics with experimental validation, a role of Kbhb sites in modulating mammalian target of rapamycin signalling and cancer cell metabolism is identified.
{"title":"Ketogenic diet reshapes cancer metabolism through lysine β-hydroxybutyrylation","authors":"Junhong Qin, Xinhe Huang, Shengsong Gou, Sitao Zhang, Yujie Gou, Qian Zhang, Hongyu Chen, Lin Sun, Miaomiao Chen, Dan Liu, Cheng Han, Min Tang, Zihao Feng, Shenghui Niu, Lin Zhao, Yingfeng Tu, Zexian Liu, Weimin Xuan, Lunzhi Dai, Da Jia, Yu Xue","doi":"10.1038/s42255-024-01093-w","DOIUrl":"10.1038/s42255-024-01093-w","url":null,"abstract":"Lysine β-hydroxybutyrylation (Kbhb) is a post-translational modification induced by the ketogenic diet (KD), a diet showing therapeutic effects on multiple human diseases. Little is known how cellular processes are regulated by Kbhb. Here we show that protein Kbhb is strongly affected by the KD through a multi-omics analysis of mouse livers. Using a small training dataset with known functions, we developed a bioinformatics method for the prediction of functionally important lysine modification sites (pFunK), which revealed functionally relevant Kbhb sites on various proteins, including aldolase B (ALDOB) Lys108. KD consumption or β-hydroxybutyrate supplementation in hepatocellular carcinoma cells increases ALDOB Lys108bhb and inhibits the enzymatic activity of ALDOB. A Kbhb-mimicking mutation (p.Lys108Gln) attenuates ALDOB activity and its binding to substrate fructose-1,6-bisphosphate, inhibits mammalian target of rapamycin signalling and glycolysis, and markedly suppresses cancer cell proliferation. Our study reveals a critical role of Kbhb in regulating cancer cell metabolism and provides a generally applicable algorithm for predicting functionally important lysine modification sites. Multi-omics analysis of mouse livers shows that protein β-hydroxybutyrylation (Kbhb) is strongly affected by the ketogenic diet. Combining bioinformatics with experimental validation, a role of Kbhb sites in modulating mammalian target of rapamycin signalling and cancer cell metabolism is identified.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918772","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 : 2024-08-09DOI: 10.1038/s42255-024-01107-7
Pedro H. V. Saavedra, Alissa J. Trzeciak, Allie Lipshutz, Andrew W. Daman, Anya J. O’Neal, Zong-Lin Liu, Zhaoquan Wang, Jesús E. Romero-Pichardo, Waleska Saitz Rojas, Giulia Zago, Marcel R. M. van den Brink, Steven Z. Josefowicz, Christopher D. Lucas, Christopher J. Anderson, Alexander Y. Rudensky, Justin S. A. Perry
The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4,5,6,7.
{"title":"Broad-spectrum antibiotics disrupt homeostatic efferocytosis","authors":"Pedro H. V. Saavedra, Alissa J. Trzeciak, Allie Lipshutz, Andrew W. Daman, Anya J. O’Neal, Zong-Lin Liu, Zhaoquan Wang, Jesús E. Romero-Pichardo, Waleska Saitz Rojas, Giulia Zago, Marcel R. M. van den Brink, Steven Z. Josefowicz, Christopher D. Lucas, Christopher J. Anderson, Alexander Y. Rudensky, Justin S. A. Perry","doi":"10.1038/s42255-024-01107-7","DOIUrl":"https://doi.org/10.1038/s42255-024-01107-7","url":null,"abstract":"<p>The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity<sup>1</sup>. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue<sup>2,3</sup>, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, <i>Timd4</i>) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease<sup>4,5,6,7</sup>.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":20.8,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141908898","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 : 2024-08-08DOI: 10.1038/s42255-024-01098-5
Yong-Uk Lee, Bennett W. Fox, Rui Guo, Brian J. Curtis, Jingfang Yu, Sookyung Kim, Shivani Nanda, Victor Baumann, L. Safak Yilmaz, Cole M. Haynes, Frank C. Schroeder, Albertha J. M. Walhout
In humans, defects in leucine catabolism cause a variety of inborn errors in metabolism. Here, we use Caenorhabditis elegans to investigate the impact of mutations in mccc-1, an enzyme that functions in leucine breakdown. Through untargeted metabolomic and transcriptomic analyses we find extensive metabolic rewiring that helps to detoxify leucine breakdown intermediates via conversion into previously undescribed metabolites and to synthesize mevalonate, an essential metabolite. We also find that the leucine breakdown product 3,3-hydroxymethylbutyrate (HMB), commonly used as a human muscle-building supplement, is toxic to C. elegans and that bacteria modulate this toxicity. Unbiased genetic screens revealed interactions between the host and microbe, where components of bacterial pyrimidine biosynthesis mitigate HMB toxicity. Finally, upregulated ketone body metabolism genes in mccc-1 mutants provide an alternative route for biosynthesis of the mevalonate precursor 3-hydroxy-3-methylglutaryl-CoA. Our work demonstrates that a complex host–bacteria interplay rewires metabolism to allow host survival when leucine catabolism is perturbed. In a C. elegans model of defective leucine catabolism, Lee et al. analyse how the complex interplay between host and bacteria rewires metabolism to enable host survival.
{"title":"Host–microbe interactions rewire metabolism in a C. elegans model of leucine breakdown deficiency","authors":"Yong-Uk Lee, Bennett W. Fox, Rui Guo, Brian J. Curtis, Jingfang Yu, Sookyung Kim, Shivani Nanda, Victor Baumann, L. Safak Yilmaz, Cole M. Haynes, Frank C. Schroeder, Albertha J. M. Walhout","doi":"10.1038/s42255-024-01098-5","DOIUrl":"10.1038/s42255-024-01098-5","url":null,"abstract":"In humans, defects in leucine catabolism cause a variety of inborn errors in metabolism. Here, we use Caenorhabditis elegans to investigate the impact of mutations in mccc-1, an enzyme that functions in leucine breakdown. Through untargeted metabolomic and transcriptomic analyses we find extensive metabolic rewiring that helps to detoxify leucine breakdown intermediates via conversion into previously undescribed metabolites and to synthesize mevalonate, an essential metabolite. We also find that the leucine breakdown product 3,3-hydroxymethylbutyrate (HMB), commonly used as a human muscle-building supplement, is toxic to C. elegans and that bacteria modulate this toxicity. Unbiased genetic screens revealed interactions between the host and microbe, where components of bacterial pyrimidine biosynthesis mitigate HMB toxicity. Finally, upregulated ketone body metabolism genes in mccc-1 mutants provide an alternative route for biosynthesis of the mevalonate precursor 3-hydroxy-3-methylglutaryl-CoA. Our work demonstrates that a complex host–bacteria interplay rewires metabolism to allow host survival when leucine catabolism is perturbed. In a C. elegans model of defective leucine catabolism, Lee et al. analyse how the complex interplay between host and bacteria rewires metabolism to enable host survival.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904471","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 : 2024-08-08DOI: 10.1038/s42255-024-01097-6
Guy A. Rutter, Anne Gresch, Luis Delgadillo Silva, Richard K. P. Benninger
Functional pancreatic islet beta cells are essential to ensure glucose homeostasis across species from zebrafish to humans. These cells show significant heterogeneity, and emerging studies have revealed that connectivity across a hierarchical network is required for normal insulin release. Here, we discuss current thinking and areas of debate around intra-islet connectivity, cellular hierarchies and potential “controlling” beta-cell populations. We focus on methodologies, including comparisons of different cell preparations as well as in vitro and in vivo approaches to imaging and controlling the activity of human and rodent islet preparations. We also discuss the analytical approaches that can be applied to live-cell data to identify and study critical subgroups of cells with a disproportionate role in control Ca2+ dynamics and thus insulin secretion (such as “first responders”, “leaders” and “hubs”, as defined by Ca2+ responses to glucose stimulation). Possible mechanisms by which this hierarchy is achieved, its physiological relevance and how its loss may contribute to islet failure in diabetes mellitus are also considered. A glossary of terms and links to computational resources are provided.
{"title":"Exploring pancreatic beta-cell subgroups and their connectivity","authors":"Guy A. Rutter, Anne Gresch, Luis Delgadillo Silva, Richard K. P. Benninger","doi":"10.1038/s42255-024-01097-6","DOIUrl":"https://doi.org/10.1038/s42255-024-01097-6","url":null,"abstract":"<p>Functional pancreatic islet beta cells are essential to ensure glucose homeostasis across species from zebrafish to humans. These cells show significant heterogeneity, and emerging studies have revealed that connectivity across a hierarchical network is required for normal insulin release. Here, we discuss current thinking and areas of debate around intra-islet connectivity, cellular hierarchies and potential “controlling” beta-cell populations. We focus on methodologies, including comparisons of different cell preparations as well as in vitro and in vivo approaches to imaging and controlling the activity of human and rodent islet preparations. We also discuss the analytical approaches that can be applied to live-cell data to identify and study critical subgroups of cells with a disproportionate role in control Ca<sup>2+</sup> dynamics and thus insulin secretion (such as “first responders”, “leaders” and “hubs”, as defined by Ca<sup>2+</sup> responses to glucose stimulation). Possible mechanisms by which this hierarchy is achieved, its physiological relevance and how its loss may contribute to islet failure in diabetes mellitus are also considered. A glossary of terms and links to computational resources are provided.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":20.8,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141904494","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 : 2024-08-07DOI: 10.1038/s42255-024-01111-x
Yu Fu
Liu et al. found that different subgroups of GABAergic neurons in mouse basal forebrain exert opposite impacts on food consumption, highlighting the complex interaction of basal forebrain and hypothalamus for regulating homeostatic and hedonic aspects of feeding.
{"title":"The dual action of basal forebrain in feeding regulation","authors":"Yu Fu","doi":"10.1038/s42255-024-01111-x","DOIUrl":"https://doi.org/10.1038/s42255-024-01111-x","url":null,"abstract":"Liu et al. found that different subgroups of GABAergic neurons in mouse basal forebrain exert opposite impacts on food consumption, highlighting the complex interaction of basal forebrain and hypothalamus for regulating homeostatic and hedonic aspects of feeding.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":20.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899474","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 : 2024-08-07DOI: 10.1038/s42255-024-01099-4
Hailan Liu, Jonathan C. Bean, Yongxiang Li, Meng Yu, Olivia Z. Ginnard, Kristine M. Conde, Mengjie Wang, Xing Fang, Hesong Liu, Longlong Tu, Na Yin, Junying Han, Yongjie Yang, Qingchun Tong, Benjamin R. Arenkiel, Chunmei Wang, Yang He, Yong Xu
Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.
{"title":"Distinct basal forebrain-originated neural circuits promote homoeostatic feeding and suppress hedonic feeding in male mice","authors":"Hailan Liu, Jonathan C. Bean, Yongxiang Li, Meng Yu, Olivia Z. Ginnard, Kristine M. Conde, Mengjie Wang, Xing Fang, Hesong Liu, Longlong Tu, Na Yin, Junying Han, Yongjie Yang, Qingchun Tong, Benjamin R. Arenkiel, Chunmei Wang, Yang He, Yong Xu","doi":"10.1038/s42255-024-01099-4","DOIUrl":"https://doi.org/10.1038/s42255-024-01099-4","url":null,"abstract":"<p>Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBB<sup>Penk</sup> neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBB<sup>Penk</sup> neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBB<sup>Penk</sup> population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":20.8,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141899372","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 : 2024-07-26DOI: 10.1038/s42255-024-01092-x
A. F. McGettrick, L. A. Bourner, F. C. Dorsey, L. A. J. O’Neill
The metabolite itaconate has emerged as an important immunoregulator with roles in antibacterial defence, inhibition of inflammation and, more recently, as an inhibitory factor in obesity. Itaconate is one of the most upregulated metabolites in inflammatory macrophages. It is produced owing to the disturbance of the tricarboxylic acid cycle and the diversion of aconitate to itaconate via the enzyme aconitate decarboxylase 1. In immunology, initial studies concentrated on the role of itaconate in inflammatory macrophages where it was shown to be inhibitory, but this has expanded as the impact of itaconate on other cell types is starting to emerge. This review focuses on itaconate as a key immunoregulatory metabolite and describes its diverse mechanisms of action and its many impacts on the immune and inflammatory responses and in cancer. We also examine the clinical relevance of this immunometabolite and its therapeutic potential for immune and inflammatory diseases.
{"title":"Metabolic Messengers: itaconate","authors":"A. F. McGettrick, L. A. Bourner, F. C. Dorsey, L. A. J. O’Neill","doi":"10.1038/s42255-024-01092-x","DOIUrl":"https://doi.org/10.1038/s42255-024-01092-x","url":null,"abstract":"<p>The metabolite itaconate has emerged as an important immunoregulator with roles in antibacterial defence, inhibition of inflammation and, more recently, as an inhibitory factor in obesity. Itaconate is one of the most upregulated metabolites in inflammatory macrophages. It is produced owing to the disturbance of the tricarboxylic acid cycle and the diversion of aconitate to itaconate via the enzyme aconitate decarboxylase 1. In immunology, initial studies concentrated on the role of itaconate in inflammatory macrophages where it was shown to be inhibitory, but this has expanded as the impact of itaconate on other cell types is starting to emerge. This review focuses on itaconate as a key immunoregulatory metabolite and describes its diverse mechanisms of action and its many impacts on the immune and inflammatory responses and in cancer. We also examine the clinical relevance of this immunometabolite and its therapeutic potential for immune and inflammatory diseases.</p>","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":20.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141764355","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 : 2024-07-25DOI: 10.1038/s42255-024-01082-z
Zimeng Cai, Qiaoling Zhong, Yanqiu Feng, Qian Wang, Zuoman Zhang, Cailv Wei, Zhinan Yin, Changhong Liang, Chong Wee Liew, Lawrence Kazak, Aaron M. Cypess, Zaiyi Liu, Kejia Cai
Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the β3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity. Creatine chemical exchange saturation transfer magnetic resonance imaging is used successfully to measure brown adipose tissue activity in rats and humans, delivering data that are consistent with [18F]fluorodeoxyglucose PET and CT measurements.
产热性棕色脂肪组织(BAT)对全身新陈代谢有积极影响。然而,体内绘制棕色脂肪组织活性图通常依赖于涉及电离辐射的技术,如[18F]氟脱氧葡萄糖([18F]FDG)正电子发射断层扫描(PET)和计算机断层扫描(CT)。在此,我们报告了一种基于肌酸化学交换饱和转移(Cr-CEST)对比的无创代谢磁共振成像(MRI)方法,用于评估啮齿类动物和人类体内 BAT 的活性。在雄性大鼠体内,单剂量的 β3-肾上腺素受体激动剂(CL 316,243)或去甲肾上腺素以及寒冷暴露会引发 Cr-CEST MRI 信号的强烈升高,这与 BAT 中肌酸浓度的[18F]FDG PET 和 CT 数据以及 1H 核磁共振测量结果一致。我们进一步表明,使用 3T 临床扫描仪,Cr-CEST MRI 可检测到人体(男性和女性)冷刺激下的 BAT 激活,其数据与 [18F]FDG PET 和 CT 测量结果相匹配。这项研究证明,Cr-CEST MRI 是一种有望在体内绘制 BAT 活动图的无创、无辐射方法。
{"title":"Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging","authors":"Zimeng Cai, Qiaoling Zhong, Yanqiu Feng, Qian Wang, Zuoman Zhang, Cailv Wei, Zhinan Yin, Changhong Liang, Chong Wee Liew, Lawrence Kazak, Aaron M. Cypess, Zaiyi Liu, Kejia Cai","doi":"10.1038/s42255-024-01082-z","DOIUrl":"10.1038/s42255-024-01082-z","url":null,"abstract":"Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the β3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity. Creatine chemical exchange saturation transfer magnetic resonance imaging is used successfully to measure brown adipose tissue activity in rats and humans, delivering data that are consistent with [18F]fluorodeoxyglucose PET and CT measurements.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11272596/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141759984","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 : 2024-07-24DOI: 10.1038/s42255-024-01081-0
Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J. Pérez-Moreno, María I. Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L. Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E. Rosales-Nieves, Alberto Pascual
Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs. Microglia rely on mitochondrial complex I during development, suggesting that complex I deficiency in microglia may have a role in primary mitochondrial diseases.
{"title":"Microglia mitochondrial complex I deficiency during development induces glial dysfunction and early lethality","authors":"Bella Mora-Romero, Nicolas Capelo-Carrasco, Juan J. Pérez-Moreno, María I. Alvarez-Vergara, Laura Trujillo-Estrada, Carmen Romero-Molina, Emilio Martinez-Marquez, Noelia Morano-Catalan, Marisa Vizuete, Jose Lopez-Barneo, Jose L. Nieto-Gonzalez, Pablo Garcia-Junco-Clemente, Javier Vitorica, Antonia Gutierrez, David Macias, Alicia E. Rosales-Nieves, Alberto Pascual","doi":"10.1038/s42255-024-01081-0","DOIUrl":"10.1038/s42255-024-01081-0","url":null,"abstract":"Primary mitochondrial diseases (PMDs) are associated with pediatric neurological disorders and are traditionally related to oxidative phosphorylation system (OXPHOS) defects in neurons. Interestingly, both PMD mouse models and patients with PMD show gliosis, and pharmacological depletion of microglia, the innate immune cells of the brain, ameliorates multiple symptoms in a mouse model. Given that microglia activation correlates with the expression of OXPHOS genes, we studied whether OXPHOS deficits in microglia may contribute to PMDs. We first observed that the metabolic rewiring associated with microglia stimulation in vitro (via IL-33 or TAU treatment) was partially changed by complex I (CI) inhibition (via rotenone treatment). In vivo, we generated a mouse model deficient for CI activity in microglia (MGcCI). MGcCI microglia showed metabolic rewiring and gradual transcriptional activation, which led to hypertrophy and dysfunction in juvenile (1-month-old) and adult (3-month-old) stages, respectively. MGcCI mice presented widespread reactive astrocytes, a decrease of synaptic markers accompanied by an increased number of parvalbumin neurons, a behavioral deficit characterized by prolonged periods of immobility, loss of weight and premature death that was partially rescued by pharmacologic depletion of microglia. Our data demonstrate that microglia development depends on mitochondrial CI and suggest a direct microglial contribution to PMDs. Microglia rely on mitochondrial complex I during development, suggesting that complex I deficiency in microglia may have a role in primary mitochondrial diseases.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":null,"pages":null},"PeriodicalIF":18.9,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141755088","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}