Pub Date : 2025-03-28DOI: 10.1016/j.metabol.2025.156240
Tetsuya Kawahara , Tetsuya Inazu , Shoichi Mizuno , Naoki Tominaga , Mikio Toda , Nagahiro Toyama , Chie Kawahara , Gen Suzuki , the DPVD Research Group
Background
The muscle-building and strengthening effects of the active form of vitamin D in humans remain unclear.
Methods
In this ancillary study of the Diabetes Prevention with active Vitamin D trial, we examined clinical and experimental aspects to investigate the effects and mechanisms of eldecalcitol, an active form of vitamin D, in preventing sarcopenia. We examined changes in molecules involved in muscle synthesis and degradation pathways in muscle samples from 32 participants before and after 1 year of eldecalcitol or placebo treatment. The protein levels of molecules involved in muscle synthesis and degradation pathways were examined using western blotting. Additionally, the skeletal muscle and body fat volumes were measured using bioelectrical impedance analysis with a body composition analyzer.
Results
We found that eldecalcitol treatment for 1 year resulted in higher phosphorylation levels of mTOR and FOXO1 signaling pathways, which are associated with increased muscle mass and strength than those with placebo treatment. Body composition measurements at 1 year showed that the eldecalcitol group had significantly higher skeletal muscle mass (1.9 % vs. −3.4 %, p = 3.26E−9) and muscle strength (4.1 % vs. −0.7 %, p = 2.57E−17), and lower fat mass (−3.2 % vs. 1.8 %, p = 1.73E−12) than those in the placebo group.
Conclusion
This study suggested that the active form of vitamin D regulates the protein synthesis and degradation pathways in human skeletal muscle and may help prevent sarcopenia. This study was registered at UMIN clinical trials registry, UMIN 000005394.
背景：活性维生素D对人体肌肉的增强作用尚不清楚。方法：在这项用活性维生素D预防糖尿病试验的辅助研究中，我们从临床和实验的角度来研究钙骨糖醇（一种活性维生素D）在预防肌肉减少症中的作用和机制。我们检查了32名参与者在接受艾尔地骨糖醇或安慰剂治疗前后1年肌肉样本中涉及肌肉合成和降解途径的分子的变化。采用western blotting检测参与肌肉合成和降解途径的分子蛋白水平。此外，骨骼肌和体脂肪体积测量使用生物电阻抗分析与身体成分分析仪。结果：我们发现，与安慰剂治疗组相比，eldecalcitol治疗1年导致mTOR和fox01信号通路的磷酸化水平升高，这与肌肉质量和力量的增加有关。1年后的身体成分测量显示，与安慰剂组相比，骨骼肌量（1.9% vs. - 3.4%, p = 3.26E−9）和肌肉力量（4.1% vs. - 0.7%, p = 2.57E−17）显著增加，脂肪量（- 3.2% vs. 1.8%, p = 1.73E−12）显著降低。结论维生素D的活性形式调节骨骼肌蛋白质合成和降解途径，可能有助于预防骨骼肌减少症。本研究已在UMIN临床试验注册中心注册，UMIN 000005394。
{"title":"Anti-sarcopenic effects of active vitamin D through modulation of anabolic and catabolic signaling pathways in human skeletal muscle: A randomized controlled trial","authors":"Tetsuya Kawahara , Tetsuya Inazu , Shoichi Mizuno , Naoki Tominaga , Mikio Toda , Nagahiro Toyama , Chie Kawahara , Gen Suzuki , the DPVD Research Group","doi":"10.1016/j.metabol.2025.156240","DOIUrl":"10.1016/j.metabol.2025.156240","url":null,"abstract":"<div><h3>Background</h3><div>The muscle-building and strengthening effects of the active form of vitamin D in humans remain unclear.</div></div><div><h3>Methods</h3><div>In this ancillary study of the Diabetes Prevention with active Vitamin D trial, we examined clinical and experimental aspects to investigate the effects and mechanisms of eldecalcitol, an active form of vitamin D, in preventing sarcopenia. We examined changes in molecules involved in muscle synthesis and degradation pathways in muscle samples from 32 participants before and after 1 year of eldecalcitol or placebo treatment. The protein levels of molecules involved in muscle synthesis and degradation pathways were examined using western blotting. Additionally, the skeletal muscle and body fat volumes were measured using bioelectrical impedance analysis with a body composition analyzer.</div></div><div><h3>Results</h3><div>We found that eldecalcitol treatment for 1 year resulted in higher phosphorylation levels of mTOR and FOXO1 signaling pathways, which are associated with increased muscle mass and strength than those with placebo treatment. Body composition measurements at 1 year showed that the eldecalcitol group had significantly higher skeletal muscle mass (1.9 % vs. −3.4 %, <em>p</em> = 3.26E−9) and muscle strength (4.1 % vs. −0.7 %, <em>p</em> = 2.57E−17), and lower fat mass (−3.2 % vs. 1.8 %, <em>p</em> = 1.73E−12) than those in the placebo group.</div></div><div><h3>Conclusion</h3><div>This study suggested that the active form of vitamin D regulates the protein synthesis and degradation pathways in human skeletal muscle and may help prevent sarcopenia. This study was registered at UMIN clinical trials registry, UMIN 000005394.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156240"},"PeriodicalIF":10.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143746469","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 : 2025-03-27DOI: 10.1016/j.metabol.2025.156242
Xinyue Sun , Jinge Wu , Huiqian Lv , Ben Wang , Xuelian Chen , Wenjing Ren , Xiulian Miao , Yan Guo , Xiaocen Kong , Huihui Xu , Zeqing Bao , Yong Xu , Zilong Li
Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global pandemic and the most critical implication for liver transplantation. In the present study, we investigated the role of CC motif chemokine ligand 7 (CCL7) in MASLD pathogenesis focusing on mechanism and translational potential. We report that CCL7 blockade with a neutralization antibody attenuated MASLD in mice. RNA-seq performed in hepatocytes identified hypermethylated in cancer 1 (HIC1) as a novel target gene responsive to CCL7 treatment. CCL7 induced HIC1 expression was mediated by steroid receptor co-activator 1 (SRC-1) in a redox-sensitive manner. Mechanistically, enhanced ROS production by CCL7 activated protein kinase C theta (PKCθ), which in turn phosphorylated SRC-1 thereby enabling SRC-1 recruitment to the Hic1 promoter. Consistently SRC-1 depletion or HIC1 depletion ameliorated MASLD in mice. Further analysis revealed that SRC-1 activated Hic1 transcription in part by recruiting protein arginine methyltransferase 4 (PRMT4) in a redox-sensitive and phosphorylation-dependent manner. Importantly, pharmaceutical inhibition of PRMT4 activity with a small-molecule compound TP-064 mitigated MASLD in mice. Finally, relevance of the CCL7-SRC-1-PRMT4-HIC1 axis was confirmed in MASLD patients. In conclusion, our data uncover a previously unrecognized redox-sensitive mechanism underlying MASLD pathogenesis and present druggable targets for MASLD intervention.
{"title":"C-C motif chemokines ligand 7 contributes to metabolic dysfunction-associated steatotic liver disease by enabling redox-sensitive induction of hypermethylated in cancer 1","authors":"Xinyue Sun , Jinge Wu , Huiqian Lv , Ben Wang , Xuelian Chen , Wenjing Ren , Xiulian Miao , Yan Guo , Xiaocen Kong , Huihui Xu , Zeqing Bao , Yong Xu , Zilong Li","doi":"10.1016/j.metabol.2025.156242","DOIUrl":"10.1016/j.metabol.2025.156242","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a global pandemic and the most critical implication for liver transplantation. In the present study, we investigated the role of C<img>C motif chemokine ligand 7 (CCL7) in MASLD pathogenesis focusing on mechanism and translational potential. We report that CCL7 blockade with a neutralization antibody attenuated MASLD in mice. RNA-seq performed in hepatocytes identified hypermethylated in cancer 1 (HIC1) as a novel target gene responsive to CCL7 treatment. CCL7 induced HIC1 expression was mediated by steroid receptor co-activator 1 (SRC-1) in a redox-sensitive manner. Mechanistically, enhanced ROS production by CCL7 activated protein kinase C theta (PKCθ), which in turn phosphorylated SRC-1 thereby enabling SRC-1 recruitment to the <em>Hic1</em> promoter. Consistently SRC-1 depletion or HIC1 depletion ameliorated MASLD in mice. Further analysis revealed that SRC-1 activated <em>Hic1</em> transcription in part by recruiting protein arginine methyltransferase 4 (PRMT4) in a redox-sensitive and phosphorylation-dependent manner. Importantly, pharmaceutical inhibition of PRMT4 activity with a small-molecule compound TP-064 mitigated MASLD in mice. Finally, relevance of the CCL7-SRC-1-PRMT4-HIC1 axis was confirmed in MASLD patients. In conclusion, our data uncover a previously unrecognized redox-sensitive mechanism underlying MASLD pathogenesis and present druggable targets for MASLD intervention.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156242"},"PeriodicalIF":10.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739814","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 : 2025-03-27DOI: 10.1016/j.metabol.2025.156241
Roxana Andreea Moldovan , Marta R. Hidalgo , Helena Castañé , Andrea Jiménez-Franco , Jorge Joven , Deborah J. Burks , Amparo Galán , Francisco García-García
Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels, and a previous step for its development. Significant sex differences have been identified in the prevalence, development, and pathophysiology of obesity and T2D; however, the underlying molecular mechanisms remain unclear. This study aims to identify sex-specific signatures in obesity and T2D and enhance our understanding of the underlying mechanisms associated with sex differences by integrating expression data.
We performed a systematic review and individual transcriptomic analysis of eight selected studies which included 302 subcutaneous adipose tissue samples. Then, we conducted different gene-level meta-analyses and functional characterizations for obesity and T2D separately, identifying common and sex-specific transcriptional profiles, many of which were previously associated with obesity or T2D.
The obesity meta-analysis yielded nineteen differentially-expressed genes from a sex-specific perspective (e.g., SPATA18, KREMEN1, NPY4R, and PRM3), while a comparison of the expression profiles between sexes in T2D prompted the identification and validation of specific transcriptomic signatures in males (SAMD9, NBPF3, LDHD, and EHD3) and females (RETN, HEY1, PLPP2, and PM20D2). At the functional level, we highlighted the fundamental role of the Wnt pathway in the development of obesity and T2D in females, and the roles of mitochondrial damage and free fatty acids in males.
Overall, our sex-specific meta-analyses supported the detection of differentially expressed genes in males and females associated with the development of obesity and further T2D development, emphasizing the relevance of sex-based information in biomedical data and opening new avenues for research.
{"title":"Landscape of sex differences in obesity and type 2 diabetes in subcutaneous adipose tissue: a systematic review and meta-analysis of transcriptomics studies","authors":"Roxana Andreea Moldovan , Marta R. Hidalgo , Helena Castañé , Andrea Jiménez-Franco , Jorge Joven , Deborah J. Burks , Amparo Galán , Francisco García-García","doi":"10.1016/j.metabol.2025.156241","DOIUrl":"10.1016/j.metabol.2025.156241","url":null,"abstract":"<div><div>Obesity represents a significant risk factor in the development of type 2 diabetes (T2D), a chronic metabolic disorder characterized by elevated blood glucose levels, and a previous step for its development. Significant sex differences have been identified in the prevalence, development, and pathophysiology of obesity and T2D; however, the underlying molecular mechanisms remain unclear. This study aims to identify sex-specific signatures in obesity and T2D and enhance our understanding of the underlying mechanisms associated with sex differences by integrating expression data.</div><div>We performed a systematic review and individual transcriptomic analysis of eight selected studies which included 302 subcutaneous adipose tissue samples. Then, we conducted different gene-level meta-analyses and functional characterizations for obesity and T2D separately, identifying common and sex-specific transcriptional profiles, many of which were previously associated with obesity or T2D.</div><div>The obesity meta-analysis yielded nineteen differentially-expressed genes from a sex-specific perspective (e.g., <em>SPATA18</em>, <em>KREMEN1</em>, <em>NPY4R</em>, and <em>PRM3</em>), while a comparison of the expression profiles between sexes in T2D prompted the identification and validation of specific transcriptomic signatures in males (<em>SAMD9</em>, <em>NBPF3</em>, <em>LDHD</em>, and <em>EHD3</em>) and females (<em>RETN</em>, <em>HEY1</em>, <em>PLPP2</em>, and <em>PM20D2</em>). At the functional level, we highlighted the fundamental role of the Wnt pathway in the development of obesity and T2D in females, and the roles of mitochondrial damage and free fatty acids in males.</div><div>Overall, our sex-specific meta-analyses supported the detection of differentially expressed genes in males and females associated with the development of obesity and further T2D development, emphasizing the relevance of sex-based information in biomedical data and opening new avenues for research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156241"},"PeriodicalIF":10.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743179","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 : 2025-03-26DOI: 10.1016/j.metabol.2025.156239
Aleix Ribas-Latre , Anne Hoffmann , Claudia Gebhardt , Juliane Weiner , Lilli Arndt , Nora Raulien , Martin Gericke , Adhideb Ghosh , Kerstin Krause , Nora Klöting , Paul T. Pfluger , Bilal N. Sheikh , Thomas Ebert , Anke Tönjes , Michael Stumvoll , Christian Wolfrum , Matthias Blüher , Ulf Wagner , Joan Vendrell , Sonia Fernández-Veledo , John T. Heiker
Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.
{"title":"The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity","authors":"Aleix Ribas-Latre , Anne Hoffmann , Claudia Gebhardt , Juliane Weiner , Lilli Arndt , Nora Raulien , Martin Gericke , Adhideb Ghosh , Kerstin Krause , Nora Klöting , Paul T. Pfluger , Bilal N. Sheikh , Thomas Ebert , Anke Tönjes , Michael Stumvoll , Christian Wolfrum , Matthias Blüher , Ulf Wagner , Joan Vendrell , Sonia Fernández-Veledo , John T. Heiker","doi":"10.1016/j.metabol.2025.156239","DOIUrl":"10.1016/j.metabol.2025.156239","url":null,"abstract":"<div><div>Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that <em>Klk7</em> deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156239"},"PeriodicalIF":10.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739929","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 : 2025-03-22DOI: 10.1016/j.metabol.2025.156237
Aleksandra Gruevska , Jack Leslie , Elena Perpiñán , Hannah Maude , Amy L. Collins , Sophia Johnson , Laila Evangelista , Eleanor Sabey , Jeremy French , Steven White , John Moir , Stuart M. Robinson , Wasfi Alrawashdeh , Rohan Thakkar , Roberta Forlano , Pinelopi Manousou , Robert Goldin , David Carling , Matthew Hoare , Mark Thursz , Zoe Hall
Background and aims
Steatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development.
Methods
We analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs).
Results
Bulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected >40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs.
Conclusions
Our spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.
{"title":"Spatial lipidomics reveals sphingolipid metabolism as anti-fibrotic target in the liver","authors":"Aleksandra Gruevska , Jack Leslie , Elena Perpiñán , Hannah Maude , Amy L. Collins , Sophia Johnson , Laila Evangelista , Eleanor Sabey , Jeremy French , Steven White , John Moir , Stuart M. Robinson , Wasfi Alrawashdeh , Rohan Thakkar , Roberta Forlano , Pinelopi Manousou , Robert Goldin , David Carling , Matthew Hoare , Mark Thursz , Zoe Hall","doi":"10.1016/j.metabol.2025.156237","DOIUrl":"10.1016/j.metabol.2025.156237","url":null,"abstract":"<div><h3>Background and aims</h3><div>Steatotic liver disease (SLD), which encompasses various causes of fat accumulation in the liver, is a major cause of liver fibrosis. Understanding the specific mechanisms of lipotoxicity, dysregulated lipid metabolism, and the role of different hepatic cell types involved in fibrogenesis is crucial for therapy development.</div></div><div><h3>Methods</h3><div>We analysed liver tissue from SLD patients and 3 mouse models. We combined bulk/spatial lipidomics, transcriptomics, imaging mass cytometry (IMC) and analysis of published spatial and single-cell RNA sequencing (scRNA-seq) data to explore the metabolic microenvironment in fibrosis. Pharmacological inhibition of sphingolipid metabolism with myriocin, fumonisin B1, miglustat and D-PDMP was carried out in hepatic stellate cells (HSCs) and human precision cut liver slices (hPCLSs).</div></div><div><h3>Results</h3><div>Bulk lipidomics revealed increased glycosphingolipids, ether lipids and saturated phosphatidylcholines in fibrotic samples. Spatial lipidomics detected >40 lipid species enriched within fibrotic regions, notably sphingomyelin (SM) 34:1. Using bulk transcriptomics (mouse) and analysis of published spatial transcriptomics data (human) we found that sphingolipid metabolism was also dysregulated in fibrosis at transcriptome level, with increased gene expression for ceramide and glycosphingolipid synthesis. Analysis of human scRNA-seq data showed that sphingolipid-related genes were widely expressed in non-parenchymal cells. By integrating spatial lipidomics with IMC of hepatic cell markers, we found excellent spatial correlation between sphingolipids, such as SM(34:1), and myofibroblasts. Inhibiting sphingolipid metabolism resulted in anti-fibrotic effects in HSCs and hPCLSs.</div></div><div><h3>Conclusions</h3><div>Our spatial multi-omics approach suggests cell type-specific mechanisms of fibrogenesis involving sphingolipid metabolism. Importantly, sphingolipid metabolic pathways are modifiable targets, which may have potential as an anti-fibrotic therapeutic strategy.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156237"},"PeriodicalIF":10.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701057","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 : 2025-03-22DOI: 10.1016/j.metabol.2025.156236
Adam Whaley-Connell , Guanghong Jia , Annayya R. Aroor , Ranganath Muniyappa , Michael A. Hill , Christos S. Mantzoros
{"title":"Insulin regulation of vessel wall function and hypertension in the metabolic syndrome; from bench to bedside and back again Revisiting the work of Dr. James R. Sowers","authors":"Adam Whaley-Connell , Guanghong Jia , Annayya R. Aroor , Ranganath Muniyappa , Michael A. Hill , Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156236","DOIUrl":"10.1016/j.metabol.2025.156236","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156236"},"PeriodicalIF":10.8,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692872","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 : 2025-03-19DOI: 10.1016/j.metabol.2025.156235
You Lee Son , Jiahui Hou , Mira Kato-Suzuki , Yuko Okamatsu-Ogura , Megumi Watase , Hiroshi Kiyonari , Toru Kondo
Aims
Epithelial V-like antigen 1 (Eva1) is a highly specific marker for brown adipose tissue (BAT) in both mice and humans, but its metabolic function remains unclear. We investigated the impact of Eva1 deletion on the development of obesity.
Methods
To assess the metabolic role of Eva1, we generated whole-body and adipocyte-specific Eva1knockout (KO) mice, which were subjected to a high-fat diet (HFD) for 12 weeks and characterized metabolic phenotypes. To further elucidate the depot-dependent impact of Eva1 deficiency, we performed histological analysis and 3′ mRNA-seq of BAT and epididymal visceral white adipose tissue (eWAT). To investigate the role of macrophage-derived Eva1 in obesity development, we transplanted wild-type (WT) or Eva1KO macrophages into Eva1KO mice fed an HFD.
Results
We found that whole-body Eva1KO mice are resistant to HFD-induced obesity, insulin resistance and visceral adipose inflammation. However, Eva1 deletion in adipocytes, both brown and white, did not phenocopy these protective effects. Notably, whole-body Eva1 deficiency triggers functional changes in eWAT, but not in BAT. These results led us to investigate a possible involvement of macrophages in Eva1-mediated obesity regulation. We found that Eva1 is expressed in macrophages and plays a role in lipopolysaccharide (LPS)-induced inflammatory responses, possibly through the direct interaction with toll-like receptor 4 (TLR4). Moreover, Eva1KO mice exhibited improved survival rates in the face of severe sepsis induced by LPS. Importantly, transplantation of WT macrophages to Eva1KO mice abolished the beneficial effects of whole-body Eva1 deletion against obesity and visceral adipose inflammation.
Conclusion
Our findings highlight macrophage-derived Eva1 as an important mediator in obesity-induced eWAT remodeling, suggesting that targeting Eva1 could offer a novel therapeutic strategy for obesity-related metabolic disorders.
{"title":"Eva1 deficiency prevents obesity-induced metabolic disorders by reducing visceral adipose dysfunction","authors":"You Lee Son , Jiahui Hou , Mira Kato-Suzuki , Yuko Okamatsu-Ogura , Megumi Watase , Hiroshi Kiyonari , Toru Kondo","doi":"10.1016/j.metabol.2025.156235","DOIUrl":"10.1016/j.metabol.2025.156235","url":null,"abstract":"<div><h3>Aims</h3><div>Epithelial V-like antigen 1 (Eva1) is a highly specific marker for brown adipose tissue (BAT) in both mice and humans, but its metabolic function remains unclear. We investigated the impact of Eva1 deletion on the development of obesity.</div></div><div><h3>Methods</h3><div>To assess the metabolic role of Eva1, we generated whole-body and adipocyte-specific Eva1<sup>knockout (KO)</sup> mice, which were subjected to a high-fat diet (HFD) for 12 weeks and characterized metabolic phenotypes. To further elucidate the depot-dependent impact of Eva1 deficiency, we performed histological analysis and 3′ mRNA-seq of BAT and epididymal visceral white adipose tissue (eWAT). To investigate the role of macrophage-derived Eva1 in obesity development, we transplanted wild-type (WT) or Eva1<sup>KO</sup> macrophages into Eva1<sup>KO</sup> mice fed an HFD.</div></div><div><h3>Results</h3><div>We found that whole-body Eva1<sup>KO</sup> mice are resistant to HFD-induced obesity, insulin resistance and visceral adipose inflammation. However, Eva1 deletion in adipocytes, both brown and white, did not phenocopy these protective effects. Notably, whole-body Eva1 deficiency triggers functional changes in eWAT, but not in BAT. These results led us to investigate a possible involvement of macrophages in Eva1-mediated obesity regulation. We found that Eva1 is expressed in macrophages and plays a role in lipopolysaccharide (LPS)-induced inflammatory responses, possibly through the direct interaction with toll-like receptor 4 (TLR4). Moreover, Eva1<sup>KO</sup> mice exhibited improved survival rates in the face of severe sepsis induced by LPS. Importantly, transplantation of WT macrophages to Eva1<sup>KO</sup> mice abolished the beneficial effects of whole-body Eva1 deletion against obesity and visceral adipose inflammation.</div></div><div><h3>Conclusion</h3><div>Our findings highlight macrophage-derived Eva1 as an important mediator in obesity-induced eWAT remodeling, suggesting that targeting Eva1 could offer a novel therapeutic strategy for obesity-related metabolic disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156235"},"PeriodicalIF":10.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674391","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 : 2025-03-18DOI: 10.1016/j.metabol.2025.156185
Robert H. Mbilinyi , Nicolaas E.P. Deutz , Clayton L. Cruthirds , Laura E. Ruebush , Tarun Sontam , Gabriella A.M. Ten Have , John J. Thaden , Mariëlle P.K.J. Engelen
Background
Exercise training is essential for pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD), yet patient responsiveness varies widely. We previously observed metabolic disturbances in amino acids critical for muscle health—such as glutamate, glutamine, branched-chain amino acids (BCAAs), and taurine—in COPD patients after an endurance exercise session, possibly related to increased energy demands and oxidative stress. However, the impact of resistance exercise on these metabolic pathways remains unclear.
Methods
We measured plasma concentration, whole-body production (WBP), and intracellular production of glutamate, glutamine, BCAAs, and taurine using stable isotope pulse techniques in 24 COPD and 25 healthy older participants. Measurements were obtained before, and at 1 and 24 h after, a resistance exercise session.
Results
At baseline, COPD participants exhibited lower WBP of glutamine, taurine, and BCAAs compared to healthy participants (p < 0.05). Resistance exercise increased WBP of glutamate by 37–42 %, glutamine by 9–10 %, and intracellular glutamate production by 37–40 %, while decreasing WBP of taurine by 7 % (all p < 0.0001). These effects persisted at 24 h post-exercise (p < 0.05). Although WBP of BCAAs remained unchanged, plasma leucine and isoleucine levels decreased by 16 % and 13 %, respectively, in COPD participants post-exercise (p < 0.05).
Conclusions
A single resistance exercise session alters glutamate-related metabolism for at least 24 h in healthy and COPD participants. A high BCAA clearance is likely required to rapidly upregulate glutamate production in COPD to meet increased energy demands, but this occurs at the cost of lowering plasma levels of BCAA necessary for muscle anabolism.
{"title":"Prolonged increase in glutamate whole body and intracellular production in older adults with COPD and healthy controls post-resistance exercise","authors":"Robert H. Mbilinyi , Nicolaas E.P. Deutz , Clayton L. Cruthirds , Laura E. Ruebush , Tarun Sontam , Gabriella A.M. Ten Have , John J. Thaden , Mariëlle P.K.J. Engelen","doi":"10.1016/j.metabol.2025.156185","DOIUrl":"10.1016/j.metabol.2025.156185","url":null,"abstract":"<div><h3>Background</h3><div>Exercise training is essential for pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD), yet patient responsiveness varies widely. We previously observed metabolic disturbances in amino acids critical for muscle health—such as glutamate, glutamine, branched-chain amino acids (BCAAs), and taurine—in COPD patients after an endurance exercise session, possibly related to increased energy demands and oxidative stress. However, the impact of resistance exercise on these metabolic pathways remains unclear.</div></div><div><h3>Methods</h3><div>We measured plasma concentration, whole-body production (WBP), and intracellular production of glutamate, glutamine, BCAAs, and taurine using stable isotope pulse techniques in 24 COPD and 25 healthy older participants. Measurements were obtained before, and at 1 and 24 h after, a resistance exercise session.</div></div><div><h3>Results</h3><div>At baseline, COPD participants exhibited lower WBP of glutamine, taurine, and BCAAs compared to healthy participants (<em>p</em> < 0.05). Resistance exercise increased WBP of glutamate by 37–42 %, glutamine by 9–10 %, and intracellular glutamate production by 37–40 %, while decreasing WBP of taurine by 7 % (all <em>p</em> < 0.0001). These effects persisted at 24 h post-exercise (<em>p</em> < 0.05). Although WBP of BCAAs remained unchanged, plasma leucine and isoleucine levels decreased by 16 % and 13 %, respectively, in COPD participants post-exercise (<em>p</em> < 0.05).</div></div><div><h3>Conclusions</h3><div>A single resistance exercise session alters glutamate-related metabolism for at least 24 h in healthy and COPD participants. A high BCAA clearance is likely required to rapidly upregulate glutamate production in COPD to meet increased energy demands, but this occurs at the cost of lowering plasma levels of BCAA necessary for muscle anabolism.</div></div><div><h3>Clinical trial registry</h3><div>Trial registration ClinicalTrials.gov: NCT02780219.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156185"},"PeriodicalIF":10.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670437","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}
Lactylation, a recently identified posttranslational modification (PTM), has emerged as a critical regulatory mechanism in cardiovascular diseases (CVDs). This PTM involves the addition of lactyl groups to lysine residues on histones and nonhistone proteins, influencing gene expression and cellular metabolism. The discovery of lactylation has revealed new directions for understanding metabolic and immune processes, particularly in the context of CVDs. This review describes the intricate roles of specific lactylated proteins and enzymes, such as H3K18, HMGB1, MCT1/4, and LDH, in the regulation of cardiovascular pathology. This study also highlights the unique impact of lactylation on myocardial hypertrophy and distinguishes it from other PTMs, such as SUMOylation and acetylation, underscoring its potential as a therapeutic target. Emerging drugs targeting lactate transporters and critical enzymes involved in lactylation offer promising avenues for novel CVD therapies. This review calls for further research to elucidate the mechanisms linking lactylation to CVDs, emphasizing the need for comprehensive studies at the molecular, cellular, and organismal levels to pave the way for innovative preventive, diagnostic, and treatment strategies in cardiovascular medicine.
{"title":"Turning sour into sweet: Lactylation modification as a promising target in cardiovascular health","authors":"Yajie Liao , Liyan Niu , Jitao Ling , Yuzhen Cui , Zixuan Huang , Jingdong Xu , Yuan Jiang , Peng Yu , Xiao Liu","doi":"10.1016/j.metabol.2025.156234","DOIUrl":"10.1016/j.metabol.2025.156234","url":null,"abstract":"<div><div>Lactylation, a recently identified posttranslational modification (PTM), has emerged as a critical regulatory mechanism in cardiovascular diseases (CVDs). This PTM involves the addition of lactyl groups to lysine residues on histones and nonhistone proteins, influencing gene expression and cellular metabolism. The discovery of lactylation has revealed new directions for understanding metabolic and immune processes, particularly in the context of CVDs. This review describes the intricate roles of specific lactylated proteins and enzymes, such as H3K18, HMGB1, MCT1/4, and LDH, in the regulation of cardiovascular pathology. This study also highlights the unique impact of lactylation on myocardial hypertrophy and distinguishes it from other PTMs, such as SUMOylation and acetylation, underscoring its potential as a therapeutic target. Emerging drugs targeting lactate transporters and critical enzymes involved in lactylation offer promising avenues for novel CVD therapies. This review calls for further research to elucidate the mechanisms linking lactylation to CVDs, emphasizing the need for comprehensive studies at the molecular, cellular, and organismal levels to pave the way for innovative preventive, diagnostic, and treatment strategies in cardiovascular medicine.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156234"},"PeriodicalIF":10.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670467","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 : 2025-03-17DOI: 10.1016/j.metabol.2025.156194
Tongtong Zhang , Zhengyun Ren , Rui Mao , Wei Yi , Bin Wang , Huawu Yang , Haibo Wang , Yanjun Liu
Obesity is a significant public health concern directly associated with adipogenesis. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of adipogenesis. However, the roles of sex-specific lncRNAs in adipose tissue are not well comprehended. In this study, we used lncRNA microarrays to profile lncRNAs expression in visceral adipose tissues from obese and lean individuals, identifying LINC00278 as significantly and exclusively expressed in males. Elevated levels of LINC00278 were associated with higher body mass index (BMI) and non-remission after bariatric surgery in individuals with obesity. Mechanistic studies further revealed that METTL14 regulates the m6A methylation of LINC00278, which in turn binds with BRG1, activating the PPAR-γ2 pathway and promoting adipogenesis. Additionally, adipose-specific LINC00278 knock-in in C57BL/6 J mice resulted in adipocyte enlargement, increased body weight, higher body fat percentage, and impaired glucose metabolism. Treatment with the BRG1 inhibitor, BRM/BRG1 ATP Inhibitor-1, significantly alleviated the obesity phenotype in these mice. Our findings highlight the critical role of LINC00278 in male adipogenesis, suggesting that targeting the LINC00278-BRG1 axis could be a potential therapeutic strategy for managing obesity and related metabolic disorders in males.
肥胖是与脂肪形成直接相关的重大公共卫生问题。长链非编码rna （lncRNAs）已成为脂肪形成的关键调控因子。然而，性别特异性lncrna在脂肪组织中的作用尚未得到很好的理解。在这项研究中，我们使用lncRNA微阵列分析了肥胖和瘦弱个体内脏脂肪组织中lncRNA的表达，发现LINC00278在男性中显著且专一表达。在肥胖患者中，LINC00278水平升高与较高的体重指数（BMI）和减肥手术后不缓解相关。机制研究进一步发现，METTL14调控LINC00278的m6A甲基化，而m6A甲基化又与BRG1结合，激活PPAR-γ - 2通路，促进脂肪形成。此外，在C57BL/6 J小鼠中，脂肪特异性LINC00278敲入导致脂肪细胞增大、体重增加、体脂率升高和糖代谢受损。BRG1抑制剂BRM/BRG1 ATP inhibitor -1治疗可显著缓解这些小鼠的肥胖表型。我们的研究结果强调了LINC00278在男性脂肪形成中的关键作用，表明靶向LINC00278- brg1轴可能是治疗男性肥胖和相关代谢紊乱的潜在治疗策略。
{"title":"LINC00278 and BRG1: A key regulatory axis in male obesity and preadipocyte adipogenesis","authors":"Tongtong Zhang , Zhengyun Ren , Rui Mao , Wei Yi , Bin Wang , Huawu Yang , Haibo Wang , Yanjun Liu","doi":"10.1016/j.metabol.2025.156194","DOIUrl":"10.1016/j.metabol.2025.156194","url":null,"abstract":"<div><div>Obesity is a significant public health concern directly associated with adipogenesis. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of adipogenesis. However, the roles of sex-specific lncRNAs in adipose tissue are not well comprehended. In this study, we used lncRNA microarrays to profile lncRNAs expression in visceral adipose tissues from obese and lean individuals, identifying LINC00278 as significantly and exclusively expressed in males. Elevated levels of LINC00278 were associated with higher body mass index (BMI) and non-remission after bariatric surgery in individuals with obesity. Mechanistic studies further revealed that METTL14 regulates the m<sup>6</sup>A methylation of LINC00278, which in turn binds with BRG1, activating the PPAR-γ2 pathway and promoting adipogenesis. Additionally, adipose-specific LINC00278 knock-in in C57BL/6 J mice resulted in adipocyte enlargement, increased body weight, higher body fat percentage, and impaired glucose metabolism. Treatment with the BRG1 inhibitor, BRM/BRG1 ATP Inhibitor-1, significantly alleviated the obesity phenotype in these mice. Our findings highlight the critical role of LINC00278 in male adipogenesis, suggesting that targeting the LINC00278-BRG1 axis could be a potential therapeutic strategy for managing obesity and related metabolic disorders in males.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"168 ","pages":"Article 156194"},"PeriodicalIF":10.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663938","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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