Pub Date : 2025-11-25DOI: 10.1016/j.metabol.2025.156458
Jinghe Li , Ruizhong Zhang , Xin Zeng , Weilong Xu , Ling Gao , Shuyun He , Bingbing Wu , Yanjie Ma , Yunzhong Nie , Jun Shirakawa , Huimin Xia , Wei Li
Background and Aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear.
Approach and results
In this study, we employed a long-term (48-week) high-fat diet-induced murine model of MASLD to recapitulate human disease progression, then treated those mice with imeglimin for 6 months to investigate its therapeutic effects. Imeglimin treatment improved insulin resistance, restored liver function, attenuated hepatic inflammation, and promoted hepatocyte viability. PEN2, a component of the γ-secretase complex, is identified as the key target of imeglimin. The therapeutic effects of imeglimin are abrogated in liver-specific Pen2-deficient mice or upon pharmacologic inhibition of AMP-activated protein kinase (AMPK), indicating that activation of PEN2-AMPK signaling is required for its beneficial effects. Furthermore, we found that imeglimin also protected human pluripotent stem cell (hPSC)-derived hepatocyte-like cells from free fatty acid (FFA)-induced lipid accumulation.
Conclusion
Collectively, our findings indicate that imeglimin ameliorates hepatic lipotoxicity by targeting PEN2 to activate AMPK axis, suggesting its potential as a new drug for MASLD treatment in the near future.
{"title":"Imeglimin ameliorates MASLD by targeting PEN2 to activate AMPK pathway","authors":"Jinghe Li , Ruizhong Zhang , Xin Zeng , Weilong Xu , Ling Gao , Shuyun He , Bingbing Wu , Yanjie Ma , Yunzhong Nie , Jun Shirakawa , Huimin Xia , Wei Li","doi":"10.1016/j.metabol.2025.156458","DOIUrl":"10.1016/j.metabol.2025.156458","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear.</div></div><div><h3>Approach and results</h3><div>In this study, we employed a long-term (48-week) high-fat diet-induced murine model of MASLD to recapitulate human disease progression, then treated those mice with imeglimin for 6 months to investigate its therapeutic effects. Imeglimin treatment improved insulin resistance, restored liver function, attenuated hepatic inflammation, and promoted hepatocyte viability. PEN2, a component of the γ-secretase complex, is identified as the key target of imeglimin. The therapeutic effects of imeglimin are abrogated in liver-specific <em>Pen2</em>-deficient mice or upon pharmacologic inhibition of AMP-activated protein kinase (AMPK), indicating that activation of PEN2-AMPK signaling is required for its beneficial effects. Furthermore, we found that imeglimin also protected human pluripotent stem cell (hPSC)-derived hepatocyte-like cells from free fatty acid (FFA)-induced lipid accumulation.</div></div><div><h3>Conclusion</h3><div>Collectively, our findings indicate that imeglimin ameliorates hepatic lipotoxicity by targeting PEN2 to activate AMPK axis, suggesting its potential as a new drug for MASLD treatment in the near future.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156458"},"PeriodicalIF":11.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615595","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 : 2025-11-24DOI: 10.1016/j.metabol.2025.156456
Gui-Yan Peng , Li-Tai Wei , Ye-Xiang Jing , Hao-Long Luo , Zi-Lun Liu , Run-Chen Wei , Jun-Jie Ning , Guang-Qi Chang , Mian Wang
Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E–deficient (ApoE−/−) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs altered intracellular lipid profiles by stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acid synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B–FASN axis drove lipid synthesis, promoted intracellular lipid storage, and facilitated the release of pro-inflammatory cytokines. Further, in cultured VSMCs, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in vitro. These findings expand the current understanding of VSMC-derived foam cell formation and suggest that targeting the TMEM41B–FASN axis may represent a promising therapeutic strategy for AS, particularly in the context of HSV infection.
{"title":"TMEM41B contributes to atherosclerosis by promoting lipid synthesis in vascular smooth muscle cells via fatty acid synthase stabilization","authors":"Gui-Yan Peng , Li-Tai Wei , Ye-Xiang Jing , Hao-Long Luo , Zi-Lun Liu , Run-Chen Wei , Jun-Jie Ning , Guang-Qi Chang , Mian Wang","doi":"10.1016/j.metabol.2025.156456","DOIUrl":"10.1016/j.metabol.2025.156456","url":null,"abstract":"<div><div>Foam cell formation has traditionally been attributed to macrophages; however, emerging evidence highlights vascular smooth muscle cells (VSMCs) as another significant contributor. Here, we found that TMEM41B is significantly upregulated in VSMCs of both human atherosclerotic (AS) lesions and murine models. Silencing TMEM41B in VSMCs of apolipoprotein E–deficient (ApoE<sup>−/−</sup>) mice markedly reduced plaque size and macrophage infiltration. Overexpressing TMEM41B in cultured VSMCs altered intracellular lipid profiles by stabilizing fatty acid synthase (FASN), a crucial enzyme in fatty acid synthesis, via inhibiting its ubiquitination and degradation. The TMEM41B–FASN axis drove lipid synthesis, promoted intracellular lipid storage, and facilitated the release of pro-inflammatory cytokines. Further, in cultured VSMCs, herpes simplex virus (HSV) infection amplified TMEM41B expression via OCT-1-mediated transcriptional activation, linking viral infection to lipid metabolic reprogramming in vitro. These findings expand the current understanding of VSMC-derived foam cell formation and suggest that targeting the TMEM41B–FASN axis may represent a promising therapeutic strategy for AS, particularly in the context of HSV infection.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156456"},"PeriodicalIF":11.9,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615594","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 : 2025-11-22DOI: 10.1016/j.metabol.2025.156454
Gaole Dai , Mingcui Luo , Shiyun Dai , Xinli Zhou , Sen Zhu , Mengxi Lu , Xiaoyi Han , Fang Yang , Ying Yu , Hui Wang , Dan Xu
Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological studies have consistently linked PCE to cognitive impairments and emotional deficits in offspring, the underlying mechanisms have long been confined to direct adenosine receptor antagonism, failing to explain the persistent neurodevelopmental consequences. Here, using cross-species models (rat PCE, astrocyte-specific Abcg1 knockout mice, and glucocorticoid-treated zebrafish) and multi-scale analyses, we demonstrate that PCE activates the maternal-fetal glucocorticoid axis, leading to dysregulation of the GR-miR-130b/301b-PPARγ signaling cascade in hippocampal astrocytes. This disrupts expression of the cholesterol transporter— ATP binding cassette subfamily G member 1 (ABCG1), impairing astrocytic cholesterol efflux and depriving neurons of cholesterol-rich microenvironments essential for synaptic development. Abcg1 knockout mice recapitulate PCE-induced synaptic defects, while astrocyte-specific ABCG1 overexpression or miR-130b/301b inhibition rescues neuronal cholesterol supply and synaptic structure. Luciferase assays confirm that miR-130b/301b directly suppress Pparγ-mediated Abcg1 transcription. Our findings identify the GR-miR-130b/301b-PPARγ-ABCG1 axis as a core mechanism of PCE-induced neurotoxicity, establishing astrocytic cholesterol transport as a potential intervention target and providing a shared molecular framework for evaluating central nervous system risks of glucocorticoid-disruptive agents.
{"title":"Prenatal caffeine exposure impairs neurodevelopment via glucocorticoid-driven epigenetic cascade suppressing astrocytic ABCG1 and cholesterol transport","authors":"Gaole Dai , Mingcui Luo , Shiyun Dai , Xinli Zhou , Sen Zhu , Mengxi Lu , Xiaoyi Han , Fang Yang , Ying Yu , Hui Wang , Dan Xu","doi":"10.1016/j.metabol.2025.156454","DOIUrl":"10.1016/j.metabol.2025.156454","url":null,"abstract":"<div><div>Prenatal caffeine exposure (PCE), stemming from widespread maternal intake of caffeine-containing substances, has emerged as a major pharmacological stressor affecting fetal neurodevelopment. Although epidemiological studies have consistently linked PCE to cognitive impairments and emotional deficits in offspring, the underlying mechanisms have long been confined to direct adenosine receptor antagonism, failing to explain the persistent neurodevelopmental consequences. Here, using cross-species models (rat PCE, astrocyte-specific <em>Abcg1</em> knockout mice, and glucocorticoid-treated zebrafish) and multi-scale analyses, we demonstrate that PCE activates the maternal-fetal glucocorticoid axis, leading to dysregulation of the GR-<em>miR-130b/301b</em>-PPARγ signaling cascade in hippocampal astrocytes. This disrupts expression of the cholesterol transporter— ATP binding cassette subfamily G member 1 (ABCG1), impairing astrocytic cholesterol efflux and depriving neurons of cholesterol-rich microenvironments essential for synaptic development. <em>Abcg1</em> knockout mice recapitulate PCE-induced synaptic defects, while astrocyte-specific ABCG1 overexpression or <em>miR-130b/301b</em> inhibition rescues neuronal cholesterol supply and synaptic structure. Luciferase assays confirm that <em>miR-130b/301b</em> directly suppress <em>Pparγ</em>-mediated <em>Abcg1</em> transcription. Our findings identify the GR-<em>miR-130b/301b</em>-PPARγ-ABCG1 axis as a core mechanism of PCE-induced neurotoxicity, establishing astrocytic cholesterol transport as a potential intervention target and providing a shared molecular framework for evaluating central nervous system risks of glucocorticoid-disruptive agents.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156454"},"PeriodicalIF":11.9,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596635","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 : 2025-11-22DOI: 10.1016/j.metabol.2025.156455
Li Jinyi , Ding Xianguang , Ding Yuhan , Huang Haoyue , Xia Zhongyu , Wang Lianhui , Jianda Xu
As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millions of people worldwide. The higher mortality and disability rates urgently require innovative therapeutic strategies. Recently, different from nanotechnology, metabolic reprogramming is believed to be associated with the occurrence and progression of various diseases (including cancer, obesity and neurodegenerative diseases). They can alter their cellular metabolism (involving glucose, lipid, and amino acid metabolism) to cope with different external stimuli and pressures. As a novel potential strategy, metabolic reprogramming also exhibits great potential to improve the wound healing of DFU. This review aims to summarize the current knowledge, biological characteristics, and underlying mechanisms of metabolic reprogramming in DFU. And we propose their potential therapeutic implications to improve wound healing and prevent complications in DFU. In addition, we also highlight the current challenges and the future perspectives.
{"title":"Metabolic reprogramming in diabetic foot ulcers: mechanisms, therapeutic implications and future perspectives","authors":"Li Jinyi , Ding Xianguang , Ding Yuhan , Huang Haoyue , Xia Zhongyu , Wang Lianhui , Jianda Xu","doi":"10.1016/j.metabol.2025.156455","DOIUrl":"10.1016/j.metabol.2025.156455","url":null,"abstract":"<div><div>As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millions of people worldwide. The higher mortality and disability rates urgently require innovative therapeutic strategies. Recently, different from nanotechnology, metabolic reprogramming is believed to be associated with the occurrence and progression of various diseases (including cancer, obesity and neurodegenerative diseases). They can alter their cellular metabolism (involving glucose, lipid, and amino acid metabolism) to cope with different external stimuli and pressures. As a novel potential strategy, metabolic reprogramming also exhibits great potential to improve the wound healing of DFU. This review aims to summarize the current knowledge, biological characteristics, and underlying mechanisms of metabolic reprogramming in DFU. And we propose their potential therapeutic implications to improve wound healing and prevent complications in DFU. In addition, we also highlight the current challenges and the future perspectives.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156455"},"PeriodicalIF":11.9,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596609","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.2025.156453
Jinxia Liu , Haifeng Wu , Ling Zhou , Qin Jin , Huoyan Ji , Baoying Hu , Hongpei Wu , Ting Chen , Xun Wang , Jianwei Hong , Rongwei Feng , Xiaojun Zhang , Jiali Zhou , Weiliang Zhang , Xu Wang , Lishuai Qu , Chunhua Wan
Background & aims
Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively investigate the role of the C-type lectin receptor DC-specific ICAM3-grabbing non-integrin (DC-SIGN) in MASLD progression.
Methods
DC-SIGN expression in liver tissues from patients with MASLD and healthy individuals was examined using immunohistochemical analyses. Immunofluorescence was used to determine DC-SIGN distribution across liver cell types. In vivo, adeno-associated virus (AAV)-mediated transduction of CD68 promoter-driven human DC-SIGN (hDC-SIGN) or a control construct was performed in mice fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD). Additionally, THP-1-differentiated macrophages were used in vitro to investigate the molecular mechanisms by which DC-SIGN modulates Toll-like receptor 4 (TLR4) endocytosis and inflammatory cytokine secretion.
Results
DC-SIGN expression was significantly reduced in liver tissues from patients with MASLD and HFHC-fed mice compared to healthy controls and NCD-fed mice. DC-SIGN predominantly co-localized with the macrophage marker CD68. Delivery of CD68 promoter-specific hDC-SIGN markedly ameliorated HFHC-induced liver lipotoxicity, steatosis, inflammation, and fibrosis. Mechanistically, DC-SIGN facilitated macrophage TLR4 endocytosis via direct binding to TLR4, suppressing MyD88-dependent pro-inflammatory responses while activating TBK1-dependent IRF3 signaling. Accordingly, LewisX (LeX)-DC-SIGN signaling reduced lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion while simultaneously enhancing anti-inflammatory IL-10 secretion.
Conclusions
DC-SIGN plays a key role in modulating TLR4-dependent inflammation in MASLD, suggesting that targeting macrophage DC-SIGN may be a promising therapeutic approach.
{"title":"DC-SIGN+ macrophages alleviate metabolic dysfunction-associated steatotic liver disease via fine-tuning TLR4 signaling and inflammatory secretory profiles","authors":"Jinxia Liu , Haifeng Wu , Ling Zhou , Qin Jin , Huoyan Ji , Baoying Hu , Hongpei Wu , Ting Chen , Xun Wang , Jianwei Hong , Rongwei Feng , Xiaojun Zhang , Jiali Zhou , Weiliang Zhang , Xu Wang , Lishuai Qu , Chunhua Wan","doi":"10.1016/j.metabol.2025.156453","DOIUrl":"10.1016/j.metabol.2025.156453","url":null,"abstract":"<div><h3>Background & aims</h3><div>Innate immune receptors play a pivotal role in modulating immune responses during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to comprehensively investigate the role of the C-type lectin receptor DC-specific ICAM3-grabbing non-integrin (DC-SIGN) in MASLD progression.</div></div><div><h3>Methods</h3><div>DC-SIGN expression in liver tissues from patients with MASLD and healthy individuals was examined using immunohistochemical analyses. Immunofluorescence was used to determine DC-SIGN distribution across liver cell types. In vivo, adeno-associated virus (AAV)-mediated transduction of CD68 promoter-driven human <em>DC-SIGN</em> (<em>hDC-SIGN</em>) or a control construct was performed in mice fed either a high-fat, high-cholesterol (HFHC) diet or a normal chow diet (NCD). Additionally, THP-1-differentiated macrophages were used in vitro to investigate the molecular mechanisms by which DC-SIGN modulates Toll-like receptor 4 (TLR4) endocytosis and inflammatory cytokine secretion.</div></div><div><h3>Results</h3><div>DC-SIGN expression was significantly reduced in liver tissues from patients with MASLD and HFHC-fed mice compared to healthy controls and NCD-fed mice. DC-SIGN predominantly co-localized with the macrophage marker CD68. Delivery of <em>CD68</em> promoter-specific <em>hDC-SIGN</em> markedly ameliorated HFHC-induced liver lipotoxicity, steatosis, inflammation, and fibrosis. Mechanistically, DC-SIGN facilitated macrophage TLR4 endocytosis via direct binding to TLR4, suppressing MyD88-dependent pro-inflammatory responses while activating TBK1-dependent IRF3 signaling. Accordingly, Lewis<sup>X</sup> (Le<sup>X</sup>)-DC-SIGN signaling reduced lipopolysaccharide (LPS)-induced pro-inflammatory cytokine secretion while simultaneously enhancing anti-inflammatory IL-10 secretion.</div></div><div><h3>Conclusions</h3><div>DC-SIGN plays a key role in modulating TLR4-dependent inflammation in MASLD, suggesting that targeting macrophage DC-SIGN may be a promising therapeutic approach.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156453"},"PeriodicalIF":11.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570289","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.2025.156451
Sibo Wang , Qian Ren , Yansheng Huang , Yibo Ma , Xuefang Zhang , Yuan Liu , Baorong He , Liang Yan
Arginine, as a semi-essential amino acid, plays a pivotal role in bone metabolism and orthopedic diseases. Beyond its function in protein synthesis, arginine serves as a crucial precursor for Nitric Oxide (NO), polyamines, and proline, profoundly influencing osteoblast differentiation, osteoclast activation, immune responses, and angiogenesis. Research indicates that abnormalities in arginine metabolism—such as imbalances in NO synthase activity, upregulation of arginase, or abnormal expression of protein arginine methyltransferases—are closely associated with the onset and progression of osteoporosis, rheumatoid arthritis, osteoarthritis, and bone tumors. Simultaneously, the arginine pathway intertwines with oxidative stress, inflammatory responses, and epigenetic regulation, forming a complex “metabolism-immunity-bone” network. In materials science, arginine has been integrated into various biomaterial systems, including Poly (lactic-co-glycolic acid) (PLGA) scaffolds, chitosan hydrogels, hydroxyapatite composites, and RGD-functionalized polymers, significantly enhancing osteogenic, angiogenic, and immunomodulatory capabilities. Despite ongoing research advancements, challenges persist in understanding the environment-dependent effects of arginine, optimizing dosage, and achieving clinical translation. This review systematically summarizes the mechanistic roles of arginine in bone metabolism regulation and its application progress in engineered materials, offering novel therapeutic insights and research directions for preventing and treating diseases such as osteoporosis, arthritis, and bone tumors.
{"title":"Emerging roles of arginine metabolism in skeletal health and disease","authors":"Sibo Wang , Qian Ren , Yansheng Huang , Yibo Ma , Xuefang Zhang , Yuan Liu , Baorong He , Liang Yan","doi":"10.1016/j.metabol.2025.156451","DOIUrl":"10.1016/j.metabol.2025.156451","url":null,"abstract":"<div><div>Arginine, as a semi-essential amino acid, plays a pivotal role in bone metabolism and orthopedic diseases. Beyond its function in protein synthesis, arginine serves as a crucial precursor for Nitric Oxide (NO), polyamines, and proline, profoundly influencing osteoblast differentiation, osteoclast activation, immune responses, and angiogenesis. Research indicates that abnormalities in arginine metabolism—such as imbalances in NO synthase activity, upregulation of arginase, or abnormal expression of protein arginine methyltransferases—are closely associated with the onset and progression of osteoporosis, rheumatoid arthritis, osteoarthritis, and bone tumors. Simultaneously, the arginine pathway intertwines with oxidative stress, inflammatory responses, and epigenetic regulation, forming a complex “metabolism-immunity-bone” network. In materials science, arginine has been integrated into various biomaterial systems, including Poly (lactic-<em>co</em>-glycolic acid) (PLGA) scaffolds, chitosan hydrogels, hydroxyapatite composites, and RGD-functionalized polymers, significantly enhancing osteogenic, angiogenic, and immunomodulatory capabilities. Despite ongoing research advancements, challenges persist in understanding the environment-dependent effects of arginine, optimizing dosage, and achieving clinical translation. This review systematically summarizes the mechanistic roles of arginine in bone metabolism regulation and its application progress in engineered materials, offering novel therapeutic insights and research directions for preventing and treating diseases such as osteoporosis, arthritis, and bone tumors.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156451"},"PeriodicalIF":11.9,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145570288","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.2025.156439
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}
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