Pub Date : 2025-11-19DOI: 10.1016/j.metabol.2025.156439
Line Pedersen , Christy M. Gliniak , Thomas Myhre Dale , Qingzhang Zhu , Chao Li , Jan-Bernd Funcke , Clair Crewe , Jiahui Luo , Lauren Palluth , Yi Zhu , Philipp E. Scherer
The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.
{"title":"Induction of Yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice","authors":"Line Pedersen , Christy M. Gliniak , Thomas Myhre Dale , Qingzhang Zhu , Chao Li , Jan-Bernd Funcke , Clair Crewe , Jiahui Luo , Lauren Palluth , Yi Zhu , Philipp E. Scherer","doi":"10.1016/j.metabol.2025.156439","DOIUrl":"10.1016/j.metabol.2025.156439","url":null,"abstract":"<div><div>The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of <em>Yy1</em> in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156439"},"PeriodicalIF":11.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564707","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 : 2025-11-19DOI: 10.1016/j.metabol.2025.156452
Shuxu Wei , Zhouwu Shu , Xinyi Li , Suiqin Zhong , Ling Xiao , Ronghuai Shen , Xiaojia Lu , Lingbin He , Youti Zhang , Yan Quan , Xianxi Huang
Background
Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood.
Methods
We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization.
Results
MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, P = 9.56 × 10−6) and metabolic syndrome risk (OR = 0.43, P = 3.90 × 10−17), while conversely, genetically predicted lower appendicular lean mass exhibited inverse associations with heart failure with heart failure and atrial fibrillation. Multi-omics identified key shared genes (ANAPC4, UNC50, TPO), with ANAPC4 methylation sites linked to CVD (cg13918811, Padj = 0.0212) and reduced muscle mass (cg04009456, Padj = 0.0049). Blood-based analyses identified 13 air pollution-associated comorbid genes, primarily responsive to PM2.5/NO2, with 11 confirmed by cross-tissue validation. Proteomics (F-statistics > 10) revealed potential targets linking CKM/sarcopenia (HP, FCGR3B, GALNT2) and CKM-events/sarcopenia (SERPINA1, FER).
Conclusion
Ambient air pollution likely promotes CKM–sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations.
{"title":"Air pollution exacerbates cardiovascular-kidney-metabolic syndrome and sarcopenia comorbidity via shared genetic-epigenetic mechanisms: A multi-omics and Mendelian Randomization study","authors":"Shuxu Wei , Zhouwu Shu , Xinyi Li , Suiqin Zhong , Ling Xiao , Ronghuai Shen , Xiaojia Lu , Lingbin He , Youti Zhang , Yan Quan , Xianxi Huang","doi":"10.1016/j.metabol.2025.156452","DOIUrl":"10.1016/j.metabol.2025.156452","url":null,"abstract":"<div><h3>Background</h3><div>Ambient air pollution aggravates cardiovascular-kidney-metabolic (CKM) disorders and sarcopenia, yet the shared genetic and epigenetic mechanisms that underlie their frequent co-occurrence remain poorly understood.</div></div><div><h3>Methods</h3><div>We integrated genome-wide association study (GWAS) data for CKM components (cardiovascular disease [CVD], chronic kidney disease [CKD], metabolic syndrome), CKM-related cardiovascular events, and sarcopenia diagnostic criteria from European-ancestry cohorts, and conducted meta-analyses harmonizing each phenotype across at least three studies. We employed Mendelian Randomization (MR) to assess potential causal links and genetic correlation analyses (global and local) to quantify shared heritability. Multi-omics analyses included two sequential phases: Phase 1 identified and validated novel shared CKM-sarcopenia genes through integrated methylation (n = 1980) and expression (n = 31,684) analyses, followed by cross-validation using two complementary transcriptome-wide association studies (TWAS). Phase 2 prioritized druggable targets through proteomic analysis across five independent cohorts (deCODE, n = 35,559; UK Biobank Pharma Proteomics Project (UKB-PPP), n = 54,219; Fenland, n = 10,708; FinnGen Olink, n = 619; FinnGen Somascan, n = 828) and integrated colocalization.</div></div><div><h3>Results</h3><div>MR suggested genetically predicted associations between sarcopenia and CKM; genetically slower walking pace was associated with higher CVD risk (OR = 0.85, <em>P</em> = 9.56 × 10<sup>−6</sup>) and metabolic syndrome risk (OR = 0.43, <em>P</em> = 3.90 × 10<sup>−17</sup>), while conversely, genetically predicted lower appendicular lean mass exhibited inverse associations with heart failure with heart failure and atrial fibrillation. Multi-omics identified key shared genes (ANAPC4, UNC50, TPO), with ANAPC4 methylation sites linked to CVD (cg13918811, <em>P</em><sub>adj</sub> = 0.0212) and reduced muscle mass (cg04009456, <em>P</em><sub>adj</sub> = 0.0049). Blood-based analyses identified 13 air pollution-associated comorbid genes, primarily responsive to PM<sub>2.5</sub>/NO<sub>2</sub>, with 11 confirmed by cross-tissue validation. Proteomics (F-statistics > 10) revealed potential targets linking CKM/sarcopenia (HP, FCGR3B, GALNT2) and CKM-events/sarcopenia (SERPINA1, FER).</div></div><div><h3>Conclusion</h3><div>Ambient air pollution likely promotes CKM–sarcopenia comorbidity chiefly via inflammatory signaling and epigenetic modifications. Our multi-omics integration reveals convergent pathways, candidate driver genes, and differential methylation sites that link these conditions. We propose these targets for environmental mitigation and molecular intervention, which require validation in diverse populations.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156452"},"PeriodicalIF":11.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573852","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 : 2025-11-15DOI: 10.1016/j.metabol.2025.156437
Xinyu Li , Shuanggang Hu , Qinling Zhu , Guangxin Yao , Jufang Yao , Jiaxing Li , Yuan Wang , Ying Ding , Jia Qi , Rui Xu , Hanting Zhao , Zhenyi Zhu , Yanzhi Du , Kang Sun , Yun Sun
{"title":"Corrigendum to “Addressing the role of 11β-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model” [Metab Clin Exp 119 (2021) 154749 1–14 [METABOLISM-D-20-01502R3]]","authors":"Xinyu Li , Shuanggang Hu , Qinling Zhu , Guangxin Yao , Jufang Yao , Jiaxing Li , Yuan Wang , Ying Ding , Jia Qi , Rui Xu , Hanting Zhao , Zhenyi Zhu , Yanzhi Du , Kang Sun , Yun Sun","doi":"10.1016/j.metabol.2025.156437","DOIUrl":"10.1016/j.metabol.2025.156437","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156437"},"PeriodicalIF":11.9,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534600","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 : 2025-11-13DOI: 10.1016/j.metabol.2025.156438
Jinfen Dai , Zixuan Zeng , Lishuan Wang , Wei Yuan , Karina Cunha e Rocha , Junho Park , Garam An , Ke Wang , Jisoo Song , Qian Xiang , Ying Duan , Chengjia Qian , Varsha Beldona , Whasun Lim , Enfu Hui , Michael Karin , Wei Ying
Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated labile iron and mitochondrial Fe2+ compared to splenic counterparts, driving high ROS and IFNγ production. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ cell iron metabolism. Ncoa4 knockout reduces labile iron, blunting ROS and IFNγ production, while Fth1 knockout elevates Fe2+ and ROS, elevating IFNγ production. CD8+ cell-specific activation of NRF2 restores iron homeostasis by upregulating ferritin and promoting oxidative detoxification, suppressing adipose tissue CD8+ T cell accumulation and IFNγ production. Finally, NRF2 overexpression in CD8+ T cells attenuates obesity-related adipose tissue inflammation and metabolic disorders. These results highlight the crucial role of labile iron supply in adipose tissue CD8+ T cell homeostasis.
{"title":"Obesity rewires CD8+ T cell iron metabolism in adipose tissue to fuel metabolic inflammation","authors":"Jinfen Dai , Zixuan Zeng , Lishuan Wang , Wei Yuan , Karina Cunha e Rocha , Junho Park , Garam An , Ke Wang , Jisoo Song , Qian Xiang , Ying Duan , Chengjia Qian , Varsha Beldona , Whasun Lim , Enfu Hui , Michael Karin , Wei Ying","doi":"10.1016/j.metabol.2025.156438","DOIUrl":"10.1016/j.metabol.2025.156438","url":null,"abstract":"<div><div>Sufficient nutrient supply is important for the maintenance of non-lymphoid tissue resident CD8+ T cell homeostasis, but the role of labile iron remains unclear. Here, we find adipose tissue CD8+ T cells exhibit elevated labile iron and mitochondrial Fe2+ compared to splenic counterparts, driving high ROS and IFNγ production. In obesity, an increase in Fe2+ influx into mitochondria enhances adipose tissue CD8+ cell functions, but weight loss normalizes CD8+ cell iron metabolism. <em>Ncoa4</em> knockout reduces labile iron, blunting ROS and IFNγ production, while <em>Fth1</em> knockout elevates Fe2+ and ROS, elevating IFNγ production. CD8+ cell-specific activation of NRF2 restores iron homeostasis by upregulating ferritin and promoting oxidative detoxification, suppressing adipose tissue CD8+ T cell accumulation and IFNγ production. Finally, NRF2 overexpression in CD8+ T cells attenuates obesity-related adipose tissue inflammation and metabolic disorders. These results highlight the crucial role of labile iron supply in adipose tissue CD8+ T cell homeostasis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156438"},"PeriodicalIF":11.9,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530875","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}
People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, insulin resistance, hypertension, and dyslipidemia). Together, CVD and metabolic syndrome constitute the cardiometabolic syndrome. Traditional CVD risk factors and high-density lipoproteins (HDL) alterations seem to contribute to the elevated CVD risk. Cumulative evidence suggests that assessing HDL function instead of HDL cholesterol levels (HDL-C) may be a better way to assess cardiometabolic risk. In HIV infection, HIV-1, ART, and the altered function of organs like the liver, gastrointestinal tract, and immune system affect the proteome, lipidome, and metabolism of HDL, ultimately leading to its dysfunction. However, the impact of altered HDL functions on PLWH remains unclear and whether HDL dysfunction reflects and/or contributes to cardiometabolic syndrome in HIV infection (bidirectional cross talk regarding how HDL function impacts the cardiometabolic syndrome and vice versa). Large cohorts of PLWH with variable CVD risk using independent assays of HDL function are needed to elucidate the bidirectional crosstalk between HDL functions and cardiometabolic syndrome. Developing novel treatments to improve HDL function in PLWH may have multiple beneficial results, reducing chronic inflammation and cardiometabolic risk in PLWH. This review aims to summarize the scientific evidence related to the role of HDL functions in HIV and how therapeutic targeting of HDL dysfunction may contribute to reduced cardiometabolic risk in PLWH.
{"title":"HDL dysfunction: a role in the pathogenesis of cardiometabolic syndrome in chronic HIV infection?","authors":"Konstantinos Markakis , Leila Fotooh Abadi , Arnaud Kombe Kombe , Martinos Christodoulides , Theodoros Kelesidis","doi":"10.1016/j.metabol.2025.156432","DOIUrl":"10.1016/j.metabol.2025.156432","url":null,"abstract":"<div><div>People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, insulin resistance, hypertension, and dyslipidemia). Together, CVD and metabolic syndrome constitute the cardiometabolic syndrome. Traditional CVD risk factors and high-density lipoproteins (HDL) alterations seem to contribute to the elevated CVD risk. Cumulative evidence suggests that assessing HDL function instead of HDL cholesterol levels (HDL-C) may be a better way to assess cardiometabolic risk. In HIV infection, HIV-1, ART, and the altered function of organs like the liver, gastrointestinal tract, and immune system affect the proteome, lipidome, and metabolism of HDL, ultimately leading to its dysfunction. However, the impact of altered HDL functions on PLWH remains unclear and whether HDL dysfunction reflects and/or contributes to cardiometabolic syndrome in HIV infection (bidirectional cross talk regarding how HDL function impacts the cardiometabolic syndrome and <em>vice versa</em>). Large cohorts of PLWH with variable CVD risk using independent assays of HDL function are needed to elucidate the bidirectional crosstalk between HDL functions and cardiometabolic syndrome. Developing novel treatments to improve HDL function in PLWH may have multiple beneficial results, reducing chronic inflammation and cardiometabolic risk in PLWH. This review aims to summarize the scientific evidence related to the role of HDL functions in HIV and how therapeutic targeting of HDL dysfunction may contribute to reduced cardiometabolic risk in PLWH.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156432"},"PeriodicalIF":11.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523957","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 : 2025-11-12DOI: 10.1016/j.metabol.2025.156436
Junpeng Long , Shasha Liu , Yaning Shi , Chanjuan Zhang , Li Qin , Qidi Ai
The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)—are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.
{"title":"Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical","authors":"Junpeng Long , Shasha Liu , Yaning Shi , Chanjuan Zhang , Li Qin , Qidi Ai","doi":"10.1016/j.metabol.2025.156436","DOIUrl":"10.1016/j.metabol.2025.156436","url":null,"abstract":"<div><div>The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)—are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156436"},"PeriodicalIF":11.9,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523936","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 : 2025-11-10DOI: 10.1016/j.metabol.2025.156435
Xing Ming , Jialin Tan , Miaomiao Yuan , Xiaoqin Ma , Feiye Zhou , Shushu Wang , Qianqian Lyu , Wenzhi Xue , Tingting Bo , Yunxia Liu , Xuejiao Zhang , Fuhua Yan , Jie Hong , Jie Zheng , Guang Ning , Weiqing Wang , Jiqiu Wang , Haipeng Sun , Libin Zhou , Xiao Wang
The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (Bckdhaf/f;RIP-Cre) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVNTRH neurons displays a similar metabolic phenotype to Bckdhaf/f;RIP-Cre mice. TRH supplementation ameliorates the abnormal phenotypes of Bckdhaf/f;RIP-Cre mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the Trh promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.
{"title":"BCAA catabolism in TRH neurons of paraventricular nucleus regulates energy expenditure","authors":"Xing Ming , Jialin Tan , Miaomiao Yuan , Xiaoqin Ma , Feiye Zhou , Shushu Wang , Qianqian Lyu , Wenzhi Xue , Tingting Bo , Yunxia Liu , Xuejiao Zhang , Fuhua Yan , Jie Hong , Jie Zheng , Guang Ning , Weiqing Wang , Jiqiu Wang , Haipeng Sun , Libin Zhou , Xiao Wang","doi":"10.1016/j.metabol.2025.156435","DOIUrl":"10.1016/j.metabol.2025.156435","url":null,"abstract":"<div><div>The role of hypothalamic branched-chain amino acid (BCAA) catabolism in the maintenance of energy homeostasis remains elusive. By using Mendelian randomization, we found that genetically predicted branched-chain keto acid dehydrogenase E1α subunit (BCKDHA) expression in the hypothalamus was negatively associated with fat mass. Hypothalamic deletion of BCKDHA (<em>Bckdha</em><sup>f/f;RIP-Cre</sup>) leads to increased fat mass, reduced energy expenditure, and blunted browning of white adipose tissue in mice, with decreases of thyrotropin-releasing hormone (TRH) expression in the paraventricular nucleus (PVN) and hypothalamic-pituitary-thyroid (HPT) axis activity. Mice with adeno-associated virus-mediated deletion of BCKDHA in the PVN<sup>TRH</sup> neurons displays a similar metabolic phenotype to <em>Bckdha</em><sup>f/f;RIP-Cre</sup> mice. TRH supplementation ameliorates the abnormal phenotypes of <em>Bckdha</em><sup>f/f;RIP-Cre</sup> mice. Defective BCAA catabolism in the hypothalamus results in hypoacetylation of histone H3 lysine 27 (H3K27) due to decreased acetyl-CoA content, reducing its binding to the <em>Trh</em> promoter. Our study highlights the crucial role of hypothalamic BCAA catabolism in maintaining energy homeostasis through HPT axis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156435"},"PeriodicalIF":11.9,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145505679","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 : 2025-11-09DOI: 10.1016/j.metabol.2025.156434
Eleonore Fröhlich , Richard Wahl
Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence following thyroidectomy has no dramatic effects. It was used in the treatment of osteoporosis but has now largely been replaced by bisphosphonates and monoclonal antibodies. However, some studies suggest that CT may have additional functions, such as those related to bone structure, osteoprotection, and pain management. This review summarizes CT synthesis and function and discusses its role and that of its precursor, procalcitonin, as biomarkers. Procalcitonin detection has advantages over some established markers in sepsis management and due to its greater stability, it is also an alternative to CT for managing medullary thyroid carcinoma. Recent research has raised the possibility that procalcitonin could serve as a direct molecular target for treating sepsis. Potential roles of various regulatory peptides released by C cells that may contribute to paracrine fine-tuning of thyroid hormone secretion by follicular thyrocytes are considered. Health-care providers should inform patients that despite optimal thyroxine replacement therapy, subtle symptoms may still occur due to the absence of C cells.
{"title":"Calcitonin and procalcitonin: Revisiting the overlooked role of C cells","authors":"Eleonore Fröhlich , Richard Wahl","doi":"10.1016/j.metabol.2025.156434","DOIUrl":"10.1016/j.metabol.2025.156434","url":null,"abstract":"<div><div>Calcitonin (CT) is a hormone produced by C cells in the thyroid gland. Its primary function is to regulate bone turnover. However, it is believed to be of little importance to human physiology because its absence following thyroidectomy has no dramatic effects. It was used in the treatment of osteoporosis but has now largely been replaced by bisphosphonates and monoclonal antibodies. However, some studies suggest that CT may have additional functions, such as those related to bone structure, osteoprotection, and pain management. This review summarizes CT synthesis and function and discusses its role and that of its precursor, procalcitonin, as biomarkers. Procalcitonin detection has advantages over some established markers in sepsis management and due to its greater stability, it is also an alternative to CT for managing medullary thyroid carcinoma. Recent research has raised the possibility that procalcitonin could serve as a direct molecular target for treating sepsis. Potential roles of various regulatory peptides released by C cells that may contribute to paracrine fine-tuning of thyroid hormone secretion by follicular thyrocytes are considered. Health-care providers should inform patients that despite optimal thyroxine replacement therapy, subtle symptoms may still occur due to the absence of C cells.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156434"},"PeriodicalIF":11.9,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145493273","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 : 2025-11-08DOI: 10.1016/j.metabol.2025.156433
Ju Zhang , Xiangfeng Guan , Mowei Kong , Meng Xia , Yang Yu , Chunxiang Zhang
Background
Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear.
Methods
This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015–July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status.
Results
A total of 18 RCTs (n = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84–0.91, P < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84–0.92, P < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83–0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78–1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89–0.99, P = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85–0.96, P < 0.01) compared with placebo.
Conclusion
In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.
背景：心血管疾病（CVD）和慢性肾脏疾病（CKD）经常共存，肥胖和2型糖尿病（T2D）是导致不良结局的主要因素。胰高血糖素样肽-1受体激动剂（GLP-1RAs）和替西肽已显示出除血糖控制外的心脏肾脏益处，但它们在代谢表型中的功效尚不清楚。方法：本综述在PROSPERO （CRD420251088042）前瞻性注册。检索PubMed， Embase， Web of Science和Cochrane Library（2015年1月- 2025年7月），比较GLP-1RAs或替西肽与安慰剂在心血管或肾脏疾病患者中的作用。根据T2D和肥胖状况进行亚组分析。结果：共纳入18项随机对照试验（n = 97,800），涉及8个GLP-1RAs和替西帕肽，主要纳入已确诊的心血管或肾脏疾病患者。GLP-1RAs显著降低了主要复合结局的风险（RR 0.88, 95 % CI 0.84-0.91, P ）结论：在心血管或肾脏疾病患者中，GLP-1RAs和替西肽提供一致的心血管和肾脏保护，可能有利于减少肥胖患者因心力衰竭住院治疗。
{"title":"GLP-1RAs and tirzepatide may reduce heart failure risk in obese but not in non-obese patients with cardiovascular or renal disease: A systematic review and meta-analysis","authors":"Ju Zhang , Xiangfeng Guan , Mowei Kong , Meng Xia , Yang Yu , Chunxiang Zhang","doi":"10.1016/j.metabol.2025.156433","DOIUrl":"10.1016/j.metabol.2025.156433","url":null,"abstract":"<div><h3>Background</h3><div>Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear.</div></div><div><h3>Methods</h3><div>This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015–July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status.</div></div><div><h3>Results</h3><div>A total of 18 RCTs (<em>n</em> = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84–0.91, <em>P</em> < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84–0.92, <em>P</em> < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83–0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78–1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89–0.99, <em>P</em> = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85–0.96, <em>P</em> < 0.01) compared with placebo.</div></div><div><h3>Conclusion</h3><div>In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156433"},"PeriodicalIF":11.9,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482508","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 : 2025-11-06DOI: 10.1016/j.metabol.2025.156429
Daosheng Ai , Baoshan Qiu , Xing-jun Chen , Fengzhi Li , Di Yao , Huijie Mi , Jun-Liszt Li , Bing Zhou , Jian Zuo , Yilong Wang , Woo-ping Ge , Wenzhi Sun
Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Microglia and their metabolic processes play a pivotal role in the pathogenesis of AIS, yet the impact and underlying mechanisms of microglial fructose metabolism remain unclear. In this study, we identified Slc2a5 (also known as Glut5), a crucial regulator of fructose metabolism in microglia, as a key factor contributing to the early progression of AIS. Conditional deletion of Slc2a5 in microglia significantly alleviated brain injury in a mouse model of AIS. Single-cell transcriptomic (scRNA-seq) analysis demonstrated that the deletion of Slc2a5 promoted the differentiation of microglia into stroke-associated subpopulations with neuroprotective properties. Moreover, in vitro experiments indicated that this microglial differentiation process was primarily mediated by the activity of pyruvate kinase M2 (PKM2). Collectively, our findings unveil a novel microglial Slc2a5-mediated fructose metabolism pathway that exacerbates brain injury after AIS. This study provides evidence for SLC2A5 as a promising therapeutic target for the clinical treatment of AIS by offering insights into its critical role in microglial metabolism and neuroprotection.
{"title":"Inhibition of microglial Slc2a5 attenuates ischemic brain injury","authors":"Daosheng Ai , Baoshan Qiu , Xing-jun Chen , Fengzhi Li , Di Yao , Huijie Mi , Jun-Liszt Li , Bing Zhou , Jian Zuo , Yilong Wang , Woo-ping Ge , Wenzhi Sun","doi":"10.1016/j.metabol.2025.156429","DOIUrl":"10.1016/j.metabol.2025.156429","url":null,"abstract":"<div><div>Acute ischemic stroke (AIS) is one of the leading causes of mortality and disability globally. Despite its complex pathological mechanisms, effective neuroprotective strategies are still lacking in clinical practice. Microglia and their metabolic processes play a pivotal role in the pathogenesis of AIS, yet the impact and underlying mechanisms of microglial fructose metabolism remain unclear. In this study, we identified <em>Slc2a5</em> (also known as <em>Glut5</em>), a crucial regulator of fructose metabolism in microglia, as a key factor contributing to the early progression of AIS. Conditional deletion of <em>Slc2a5</em> in microglia significantly alleviated brain injury in a mouse model of AIS. Single-cell transcriptomic (scRNA-seq) analysis demonstrated that the deletion of <em>Slc2a5</em> promoted the differentiation of microglia into stroke-associated subpopulations with neuroprotective properties. Moreover, in vitro experiments indicated that this microglial differentiation process was primarily mediated by the activity of pyruvate kinase M2 (PKM2). Collectively, our findings unveil a novel microglial <em>Slc2a5</em>-mediated fructose metabolism pathway that exacerbates brain injury after AIS. This study provides evidence for SLC2A5 as a promising therapeutic target for the clinical treatment of AIS by offering insights into its critical role in microglial metabolism and neuroprotection.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156429"},"PeriodicalIF":11.9,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476654","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}
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