Type 2 diabetes (T2D) manifests as profound systemic metabolic dysregulation. Mounting evidence indicates T2D significantly impairs T cell immunity, compromising both protective immune responses and immune homeostasis. This dysfunction stems from the multitude roles of metabolites in T cell biology: energy substrates, signaling molecules, and epigenetic regulators. In this review, we synthesize current evidence on how the metabolic hallmarks of T2D (hyperglycemia, hyperinsulinemia, and dyslipidemia) reprogram T cell metabolism and their functionalities. Notably, most patients with T2D receive combination antidiabetic therapies which not only correct systemic metabolism but also exert direct immunomodulatory effects on T cells. Unraveling the interplay between disease-driven metabolic perturbations and pharmacologically induced immunomodulation is essential to advance therapeutic strategies that restore immune competence while preserving immunoregulatory balance.
{"title":"Metabolic hallmarks of type 2 diabetes compromise T cell function.","authors":"Yuteng Liang,Weixin Chen,Qier Gao,Kathryn Choon-Beng Tan,Chi-Ho Lee,Guang Sheng Ling","doi":"10.1016/j.tem.2025.08.005","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.005","url":null,"abstract":"Type 2 diabetes (T2D) manifests as profound systemic metabolic dysregulation. Mounting evidence indicates T2D significantly impairs T cell immunity, compromising both protective immune responses and immune homeostasis. This dysfunction stems from the multitude roles of metabolites in T cell biology: energy substrates, signaling molecules, and epigenetic regulators. In this review, we synthesize current evidence on how the metabolic hallmarks of T2D (hyperglycemia, hyperinsulinemia, and dyslipidemia) reprogram T cell metabolism and their functionalities. Notably, most patients with T2D receive combination antidiabetic therapies which not only correct systemic metabolism but also exert direct immunomodulatory effects on T cells. Unraveling the interplay between disease-driven metabolic perturbations and pharmacologically induced immunomodulation is essential to advance therapeutic strategies that restore immune competence while preserving immunoregulatory balance.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-10DOI: 10.1016/j.tem.2025.09.002
Yun-Zi Mao,Shi-Min Zhao
Metabolites are donors of epigenetic modifications. Zhao et al. demonstrated that an ELMSAN1 regulated nuclear pyruvate dehydrogenase complex (nPDC) generates an independent nuclear acetyl-CoA pool dedicated to histone acetylation. Disrupting ELMSAN1-nPDC interaction reprograms histone acetylation and impedes tumor progression, highlighting the regulation of epigenetics and cell signaling by targeting compartmentalized metabolism.
{"title":"Target compartmentalized metabolism to regulate epigenetics.","authors":"Yun-Zi Mao,Shi-Min Zhao","doi":"10.1016/j.tem.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.tem.2025.09.002","url":null,"abstract":"Metabolites are donors of epigenetic modifications. Zhao et al. demonstrated that an ELMSAN1 regulated nuclear pyruvate dehydrogenase complex (nPDC) generates an independent nuclear acetyl-CoA pool dedicated to histone acetylation. Disrupting ELMSAN1-nPDC interaction reprograms histone acetylation and impedes tumor progression, highlighting the regulation of epigenetics and cell signaling by targeting compartmentalized metabolism.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"79 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-08DOI: 10.1016/j.tem.2025.08.006
Francisco M Acosta,Johanna Örling,Marko Salmi,Kirsi A Virtanen
Advances in the immunometabolism field have shown that infiltrated immune cells play a pivotal role in the development and function of thermogenic adipose tissue (TAT), including brown and beige fat. However, scarce research has focused on the role that organized lymphoid structures, like lymph nodes and lymphatics vessels, may exert on TAT. In this review we summarize the evidence suggesting that a significant link exists between the lymphoid tissues and adipose tissue, and we describe the most important in vitro and in vivo findings indicating that organized lymphoid tissues also play an important role in TAT biogenesis and function, raising relevant questions which are still unsolved in this emerging field.
{"title":"The interplay between organized lymphoid structures and thermogenic adipose tissue.","authors":"Francisco M Acosta,Johanna Örling,Marko Salmi,Kirsi A Virtanen","doi":"10.1016/j.tem.2025.08.006","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.006","url":null,"abstract":"Advances in the immunometabolism field have shown that infiltrated immune cells play a pivotal role in the development and function of thermogenic adipose tissue (TAT), including brown and beige fat. However, scarce research has focused on the role that organized lymphoid structures, like lymph nodes and lymphatics vessels, may exert on TAT. In this review we summarize the evidence suggesting that a significant link exists between the lymphoid tissues and adipose tissue, and we describe the most important in vitro and in vivo findings indicating that organized lymphoid tissues also play an important role in TAT biogenesis and function, raising relevant questions which are still unsolved in this emerging field.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"87 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-06DOI: 10.1016/j.tem.2025.08.008
Nadia Rashid,Kavaljit H Chhabra
Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.
{"title":"Contribution of metabolism-independent glucose sensing to metabolic homeostasis.","authors":"Nadia Rashid,Kavaljit H Chhabra","doi":"10.1016/j.tem.2025.08.008","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.008","url":null,"abstract":"Glucose sensing and signaling are central to cellular metabolic machinery for the regulation of metabolic homeostasis. Glucose sensing has been almost always assumed to be coupled with glucose metabolism; however, recent findings have unraveled metabolism-independent sensing mechanisms. Here, we discuss whether glucose transporters (GLUTs) and sodium-glucose co-transporters (SGLTs) may also function as glucose sensors independent of their roles in transporting glucose. Moreover, we review the emerging roles of G protein-coupled receptors (GPCRs) in sensing glucose and, consequently, initiating its signaling pathways in a cell-specific manner. Altogether, this review offers insights into the newly identified glucose sensing mechanisms and highlights the therapeutic potential of targeting the downstream glucose signaling pathways for more efficient treatment of diabetes, obesity, and their complications.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145008719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-04DOI: 10.1016/j.tem.2025.08.007
Antonella Tramutola,Fabio Di Domenico,Marzia Perluigi,Eugenio Barone
Biliverdin reductase-A (BVRA) is a pleiotropic enzyme traditionally known for its antioxidant role in the heme degradation pathway. Recent findings have redefined BVRA as a master regulator of insulin signaling, acting as a kinase, scaffold, and redox-sensitive integrator of metabolic cues. BVRA modulates key nodes of the insulin cascade and sustains mitochondrial and synaptic function. Notably, BVRA loss precedes the accumulation of canonical markers of insulin resistance both peripherally and in the brain. Here we discuss how BVRA could represent an early cross-tissue biomarker of metabolic vulnerability. Its dysfunction contributes to mitochondrial stress, impaired proteostasis, and cognitive decline, thus linking metabolic and neurodegenerative disorders.
胆绿素还原酶- a （BVRA）是一种多效酶，传统上以其在血红素降解途径中的抗氧化作用而闻名。最近的研究发现将BVRA重新定义为胰岛素信号的主要调节因子，作为激酶、支架和氧化还原敏感的代谢信号整合器。BVRA调节胰岛素级联的关键节点并维持线粒体和突触功能。值得注意的是，BVRA的丧失先于胰岛素抵抗的典型标志物的积累，这些标志物在外周和大脑中都是如此。在这里，我们讨论了BVRA如何代表代谢易损性的早期跨组织生物标志物。它的功能障碍导致线粒体应激、蛋白质平衡受损和认知能力下降，因此与代谢和神经退行性疾病有关。
{"title":"Biliverdin reductase-A is a key modulator in insulin signaling and metabolism.","authors":"Antonella Tramutola,Fabio Di Domenico,Marzia Perluigi,Eugenio Barone","doi":"10.1016/j.tem.2025.08.007","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.007","url":null,"abstract":"Biliverdin reductase-A (BVRA) is a pleiotropic enzyme traditionally known for its antioxidant role in the heme degradation pathway. Recent findings have redefined BVRA as a master regulator of insulin signaling, acting as a kinase, scaffold, and redox-sensitive integrator of metabolic cues. BVRA modulates key nodes of the insulin cascade and sustains mitochondrial and synaptic function. Notably, BVRA loss precedes the accumulation of canonical markers of insulin resistance both peripherally and in the brain. Here we discuss how BVRA could represent an early cross-tissue biomarker of metabolic vulnerability. Its dysfunction contributes to mitochondrial stress, impaired proteostasis, and cognitive decline, thus linking metabolic and neurodegenerative disorders.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"141 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145003193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-30DOI: 10.1016/j.tem.2025.08.004
Andrea Dell'Olio,Franco Biasioli,Vincenzo Fogliano,Josep Rubert
The human gut microbiome is a complex microbial ecosystem which has a profound impact on host health and disease. The research focus in this area is rapidly moving from taxonomy to functionality, elucidating the biological role of small molecules produced by the gut microbiome in regulating host metabolism. Among these, microbial volatile organic compounds (mVOCs) play several roles in bacterial communication and microbe-host signaling. Volatilomics, the comprehensive study of volatile metabolites, is emerging as a powerful tool for discovering and investigating these interactions. In this review we examine the current understanding of mVOCs in the gut and highlight how dedicated in vitro and ex vivo volatilomics experiments, alongside in vivo studies, can uncover the biological roles for these emerging small molecules.
{"title":"Decoding microbial volatile signals in host-microbiome crosstalk.","authors":"Andrea Dell'Olio,Franco Biasioli,Vincenzo Fogliano,Josep Rubert","doi":"10.1016/j.tem.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.004","url":null,"abstract":"The human gut microbiome is a complex microbial ecosystem which has a profound impact on host health and disease. The research focus in this area is rapidly moving from taxonomy to functionality, elucidating the biological role of small molecules produced by the gut microbiome in regulating host metabolism. Among these, microbial volatile organic compounds (mVOCs) play several roles in bacterial communication and microbe-host signaling. Volatilomics, the comprehensive study of volatile metabolites, is emerging as a powerful tool for discovering and investigating these interactions. In this review we examine the current understanding of mVOCs in the gut and highlight how dedicated in vitro and ex vivo volatilomics experiments, alongside in vivo studies, can uncover the biological roles for these emerging small molecules.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-29DOI: 10.1016/j.tem.2025.08.001
Miaochun Xu,Yang Yu,Canhui Cao
Taurine is a conditionally essential amino acid with paradoxical roles in cancer, as both tumor and immune cells rely on it for vital functions. Here, we discuss the emerging context-dependent functions of taurine and propose therapeutic strategies that leverage or inhibit its metabolism to modulate cancer progression and immunity.
{"title":"The dual role of taurine in cancer and immune metabolism.","authors":"Miaochun Xu,Yang Yu,Canhui Cao","doi":"10.1016/j.tem.2025.08.001","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.001","url":null,"abstract":"Taurine is a conditionally essential amino acid with paradoxical roles in cancer, as both tumor and immune cells rely on it for vital functions. Here, we discuss the emerging context-dependent functions of taurine and propose therapeutic strategies that leverage or inhibit its metabolism to modulate cancer progression and immunity.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-28DOI: 10.1016/j.tem.2025.08.003
David S Umbaugh,Anna Mae Diehl,Kuo Du
Hepatocyte senescence is increasingly recognized as a key contributor to liver pathophysiology. While traditionally viewed as a state of permanent growth arrest, hepatocyte senescence is now understood to be more dynamic and potentially reversible, particularly during liver repair. In this opinion article, we propose reframing senescence as a continuum rather than a terminal fate. We focus on early stress-responsive states, especially those marked by p21 expression, which may be adaptive or pro-regenerative depending on the context. We highlight the roles of p21-associated secretory phenotypes (PASPs), senescence-associated secretory phenotypes (SASPs), epithelial plasticity, and partial epithelial-to-mesenchymal transition (EMT) in modulating hepatocyte behavior, immune surveillance, and cancer risk. Viewing hepatocyte senescence as a trajectory opens new opportunities for context-specific and temporally targeted therapeutic strategies in liver disease.
{"title":"Redefining senescence through hepatocyte fate changes in liver diseases.","authors":"David S Umbaugh,Anna Mae Diehl,Kuo Du","doi":"10.1016/j.tem.2025.08.003","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.003","url":null,"abstract":"Hepatocyte senescence is increasingly recognized as a key contributor to liver pathophysiology. While traditionally viewed as a state of permanent growth arrest, hepatocyte senescence is now understood to be more dynamic and potentially reversible, particularly during liver repair. In this opinion article, we propose reframing senescence as a continuum rather than a terminal fate. We focus on early stress-responsive states, especially those marked by p21 expression, which may be adaptive or pro-regenerative depending on the context. We highlight the roles of p21-associated secretory phenotypes (PASPs), senescence-associated secretory phenotypes (SASPs), epithelial plasticity, and partial epithelial-to-mesenchymal transition (EMT) in modulating hepatocyte behavior, immune surveillance, and cancer risk. Viewing hepatocyte senescence as a trajectory opens new opportunities for context-specific and temporally targeted therapeutic strategies in liver disease.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-28DOI: 10.1016/j.tem.2025.08.002
Ibrahim H Ibrahim,Cheng-Han Lin,Ming Zhou,Jer-Yen Yang,Robert W Sobol,Ming Tan
Over the past decade, our understanding of cancer metabolism has advanced significantly, revealing a complex and dynamic landscape of metabolic reprogramming that facilitates tumor progression and promotes therapeutic resistance. To survive under stressful conditions, cancer cells undergo crucial metabolic adaptations while also creating vulnerabilities that can be exploited for therapeutic purposes. Here, we discuss the evolving understanding of cancer cell metabolic adaptation in the tumor environment and the recent advances in identifying potential therapeutic mechanisms, including synthetic lethality, post-translational modifications (PTMs), as well as the interplay between metabolism and epigenetics. Furthermore, we discuss the integration of metabolic targeting with immune-based therapies and provide insights underscoring the potential of metabolic interventions to resensitize drug-resistant cancers and enhance efficacy for cancer treatment.
{"title":"Exploiting metabolic vulnerabilities to improve cancer therapeutics.","authors":"Ibrahim H Ibrahim,Cheng-Han Lin,Ming Zhou,Jer-Yen Yang,Robert W Sobol,Ming Tan","doi":"10.1016/j.tem.2025.08.002","DOIUrl":"https://doi.org/10.1016/j.tem.2025.08.002","url":null,"abstract":"Over the past decade, our understanding of cancer metabolism has advanced significantly, revealing a complex and dynamic landscape of metabolic reprogramming that facilitates tumor progression and promotes therapeutic resistance. To survive under stressful conditions, cancer cells undergo crucial metabolic adaptations while also creating vulnerabilities that can be exploited for therapeutic purposes. Here, we discuss the evolving understanding of cancer cell metabolic adaptation in the tumor environment and the recent advances in identifying potential therapeutic mechanisms, including synthetic lethality, post-translational modifications (PTMs), as well as the interplay between metabolism and epigenetics. Furthermore, we discuss the integration of metabolic targeting with immune-based therapies and provide insights underscoring the potential of metabolic interventions to resensitize drug-resistant cancers and enhance efficacy for cancer treatment.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144960025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1016/j.tem.2025.07.008
Jianxin Jia, Zhehui Li, Liyuan Zhao, Mingyu Li
Glucagon receptor (GCGR) antagonism improves glycemic control; however, it also brings adverse effects through unclear underlying mechanisms. Here, we summarize emerging findings about the impact of GCGR blockade on α cells and discuss the challenges and potential of GCGR antagonism on clinical application.
{"title":"Glucagon receptor antagonism requires further mechanistic attention on α-cell physiology","authors":"Jianxin Jia, Zhehui Li, Liyuan Zhao, Mingyu Li","doi":"10.1016/j.tem.2025.07.008","DOIUrl":"https://doi.org/10.1016/j.tem.2025.07.008","url":null,"abstract":"Glucagon receptor (GCGR) antagonism improves glycemic control; however, it also brings adverse effects through unclear underlying mechanisms. Here, we summarize emerging findings about the impact of GCGR blockade on α cells and discuss the challenges and potential of GCGR antagonism on clinical application.","PeriodicalId":23301,"journal":{"name":"Trends in Endocrinology & Metabolism","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144901564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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