Pub Date : 2025-11-29DOI: 10.1016/j.molmet.2025.102293
Zheng Ge , Zitian Liu , Shuohui Dong , Xiang Zhao , Guangwei Yang , Ao Yu , Wei Guo , Xiang Zhang , Qunzheng Wu , Kexin Wang
High-fat diet (HFD) promotes adipose tissue senescence, which in turn disrupts insulin-mediated glycemic homeostasis. The underlying mechanisms remain unclear. Through clinical survey data, animal models, and primary adipose-derived mesenchymal stem cells (ADSC), we investigated how dietary patterns influence adipocyte senescence. We found that elevated fatty acid levels enhance the interaction between the E3 ubiquitin ligase TRIP12 and Cyclin-dependent kinase 4 (CDK4) in ADSCs, triggering CDK4 ubiquitination and degradation. As a process associated with this disruption in cell cycle progression, cellular senescence may represent a key outcome. Consequently, senescent ADSC-derived mature adipocytes (ADSC-MA) exhibit impaired insulin-stimulated GLUT4 membrane translocation and reduced glucose uptake. In contrast, within an HFD setting, dietary fiber supplementation is associated with the reversal of cellular senescence. The gut microbiota–short-chain fatty acids (SCFAs) axis may be involved in the restoration of cell cycle progression and the amelioration of ADSC senescence, correlating with a partial recovery of glucose uptake capacity in ADSC-MAs. Our study highlights potential strategies to reverse cellular senescence and identifies promising therapeutic targets for impaired glucose tolerance.
{"title":"High-fat diet induces senescence in ADSCs via CDK4 ubiquitination-mediated cell cycle disruption, contributing to impaired glucose tolerance","authors":"Zheng Ge , Zitian Liu , Shuohui Dong , Xiang Zhao , Guangwei Yang , Ao Yu , Wei Guo , Xiang Zhang , Qunzheng Wu , Kexin Wang","doi":"10.1016/j.molmet.2025.102293","DOIUrl":"10.1016/j.molmet.2025.102293","url":null,"abstract":"<div><div>High-fat diet (HFD) promotes adipose tissue senescence, which in turn disrupts insulin-mediated glycemic homeostasis. The underlying mechanisms remain unclear. Through clinical survey data, animal models, and primary adipose-derived mesenchymal stem cells (ADSC), we investigated how dietary patterns influence adipocyte senescence. We found that elevated fatty acid levels enhance the interaction between the E3 ubiquitin ligase TRIP12 and Cyclin-dependent kinase 4 (CDK4) in ADSCs, triggering CDK4 ubiquitination and degradation. As a process associated with this disruption in cell cycle progression, cellular senescence may represent a key outcome. Consequently, senescent ADSC-derived mature adipocytes (ADSC-MA) exhibit impaired insulin-stimulated GLUT4 membrane translocation and reduced glucose uptake. In contrast, within an HFD setting, dietary fiber supplementation is associated with the reversal of cellular senescence. The gut microbiota–short-chain fatty acids (SCFAs) axis may be involved in the restoration of cell cycle progression and the amelioration of ADSC senescence, correlating with a partial recovery of glucose uptake capacity in ADSC-MAs. Our study highlights potential strategies to reverse cellular senescence and identifies promising therapeutic targets for impaired glucose tolerance.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102293"},"PeriodicalIF":6.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1016/j.molmet.2025.102295
Shruti Bhargava , Zhuangting Rao , Raymond Vanholder , Frank Tacke , Heidi Noels , Vera Jankowski , Juliane Hermann , Joachim Jankowski
Introduction
The current understanding of interactions and crosstalk among essential organs remains incomplete, mainly due to the limitations of studies on the systemic mechanisms at play. The gut and the liver are essential for the functioning of the entire body, and their derived mediators circulate through blood or lymph, impacting other organs like the brain, heart, and kidneys.
Aim
This publication reviews gut-liver-derived mediators, which were tested and validated in vivo in humans and rodents, together with the current knowledge of their systemic effects on key vital organs.
Method
Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science.
Results
During this systematic analysis, 28 gut-liver-derived mediators were identified from 52 publications and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones, (d) lipids and (e) proteins. Additionally, the mechanism of action for each of these molecules was specified, aimed at providing a mechanistic overview of their effects on the brain, heart, and kidneys.
Discussion
The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression.
Conclusion
Our research shows the necessity of a thorough examination of these mediators, exploring their diagnostic and therapeutic potential in a holistic multi-organ setting, to elucidate inter-organ crosstalk.
目前对重要器官之间的相互作用和串扰的理解仍然不完整，主要是由于对系统机制的研究有限。肠道和肝脏对整个身体的功能至关重要，它们衍生的介质通过血液或淋巴循环，影响其他器官，如大脑、心脏和肾脏。本出版物回顾了在人类和啮齿类动物体内进行测试和验证的肠道-肝脏来源的介质，以及它们对关键重要器官的系统性影响的最新知识。截至2025年2月发表的基于临床试验或体内实验模型的原创文章，从PubMed和Web of Science检索。在这项系统分析中，从52份出版物中鉴定出28种肠-肝源性介质，并根据其分子特征将其分为五组：(a)低分子量代谢物，(b)内毒素，(c)激素，(d)脂质和(e)蛋白质。此外，每种分子的作用机制都被指定，旨在提供它们对大脑、心脏和肾脏影响的机制概述。已确定的介质对合并症的影响多种多样，有时相互冲突，因此需要进一步研究确定影响疾病发生和进展的关键机制。我们的研究表明，有必要对这些介质进行彻底的检查，探索它们在整体多器官环境中的诊断和治疗潜力，以阐明器官间的串扰。
{"title":"The impact of gut-liver-derived mediators on the organ crosstalk with brain, heart, and kidney: A systematic review","authors":"Shruti Bhargava , Zhuangting Rao , Raymond Vanholder , Frank Tacke , Heidi Noels , Vera Jankowski , Juliane Hermann , Joachim Jankowski","doi":"10.1016/j.molmet.2025.102295","DOIUrl":"10.1016/j.molmet.2025.102295","url":null,"abstract":"<div><h3>Introduction</h3><div>The current understanding of interactions and crosstalk among essential organs remains incomplete, mainly due to the limitations of studies on the systemic mechanisms at play. The gut and the liver are essential for the functioning of the entire body, and their derived mediators circulate through blood or lymph, impacting other organs like the brain, heart, and kidneys.</div></div><div><h3>Aim</h3><div>This publication reviews gut-liver-derived mediators, which were tested and validated <em>in vivo</em> in humans and rodents, together with the current knowledge of their systemic effects on key vital organs.</div></div><div><h3>Method</h3><div>Original articles published up to February 2025, based on clinical trials or in vivo experimental models, were retrieved from PubMed and Web of Science.</div></div><div><h3>Results</h3><div>During this systematic analysis, 28 gut-liver-derived mediators were identified from 52 publications and classified into five distinct groups based on their molecular characteristics: (a) low molecular weight metabolites, (b) endotoxins, (c) hormones, (d) lipids and (e) proteins. Additionally, the mechanism of action for each of these molecules was specified, aimed at providing a mechanistic overview of their effects on the brain, heart, and kidneys.</div></div><div><h3>Discussion</h3><div>The diverse and occasionally conflicting impact of the identified mediators on comorbidities necessitates further investigations pinpointing key mechanisms influencing disease genesis and progression.</div></div><div><h3>Conclusion</h3><div>Our research shows the necessity of a thorough examination of these mediators, exploring their diagnostic and therapeutic potential in a holistic multi-organ setting, to elucidate inter-organ crosstalk.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102295"},"PeriodicalIF":6.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1016/j.molmet.2025.102294
Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , Kei Sakamoto
Objectives
Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.
Methods
Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1−/−/γ3−/−) and single knockout (imγ1−/− and imγ3−/−) mice were generated. Ex vivo glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and in vivo MK-8722-induced blood glucose lowering was assessed.
Results
snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. Ex vivo, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1−/−/γ3−/− muscle, and MK-8722-induced blood glucose lowering was significantly blunted in vivo. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3−/−, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1−/− mice.
Conclusions
While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.
{"title":"Common and distinct roles of AMPKγ isoforms in small-molecule activator-stimulated glucose uptake in mouse skeletal muscle","authors":"Dipsikha Biswas , Ever Espino-Gonzalez , Danial Ahwazi , Jordana B. Freemantle , Amy M. Ehrlich , Charline Jomard , Jonas Brorson , Agnete N. Schou , Jean Farup , Julien Gondin , Jesper Just , Marc Foretz , Jonas T. Treebak , Marianne Agerholm , Kei Sakamoto","doi":"10.1016/j.molmet.2025.102294","DOIUrl":"10.1016/j.molmet.2025.102294","url":null,"abstract":"<div><h3>Objectives</h3><div>Small-molecule activators targeting the allosteric drug and metabolite (ADaM) site of AMPK enhance insulin-independent glucose uptake in skeletal muscle and lower glucose in preclinical models of hyperglycemia. The regulatory AMPKγ subunit plays a central role in energy sensing. While the skeletal muscle-selective γ3 isoform is essential for AMP/ZMP-induced glucose uptake, it is dispensable for ADaM site-binding activators. We hypothesized that the predominant γ1 isoform is required for ADaM site activator-stimulated glucose uptake in skeletal muscle.</div></div><div><h3>Methods</h3><div>Single-nucleus RNA sequencing (snRNA-seq) was performed on mouse and human skeletal muscle mapping AMPK subunit isoform distribution across resident cell types. To determine γ isoform-specific requirements for activator-stimulated glucose uptake, skeletal muscle-specific inducible AMPKγ1/γ3 double knockout (imγ1<sup>−/−</sup>/γ3<sup>−/−</sup>) and single knockout (imγ1<sup>−/−</sup> and imγ3<sup>−/−</sup>) mice were generated<em>. Ex vivo</em> glucose uptake was measured following treatment with AICAR (AMP-mimetic) or MK-8722 (ADaM site activator), and <em>in vivo</em> MK-8722-induced blood glucose lowering was assessed.</div></div><div><h3>Results</h3><div>snRNA-seq revealed distinct AMPK isoform distribution: γ1 was ubiquitously expressed, whereas γ3 was enriched in glycolytic myofibers in both mouse and human skeletal muscle. <em>Ex vivo</em>, glucose uptake stimulated by either AICAR or MK-8722 was severely blunted in imγ1<sup>−/−</sup>/γ3<sup>−/−</sup> muscle, and MK-8722-induced blood glucose lowering was significantly blunted <em>in vivo</em>. AICAR but not MK-8722-stimulated muscle glucose uptake was abolished in imγ3<sup>−/−</sup>, whereas both activators fully retained effects on glucose uptake and glucose lowering in imγ1<sup>−/−</sup> mice.</div></div><div><h3>Conclusions</h3><div>While γ1 predominates in stabilizing the AMPKα2β2γ1 complex, it is dispensable for AMPK activator-stimulated glucose uptake in skeletal muscle, whether mediated via the nucleotide-binding or ADaM site.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102294"},"PeriodicalIF":6.6,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145654769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1016/j.molmet.2025.102291
Manu V. Chakravarthy , Ruben Rodriguez , Anne Hergarden , Michael A. Elliott , Juan P. Frias , Federico A. Argüelles-Tello , Edgar Tenorio , Jonathan E. Rankin , Jingtao Wu , Shyam Krishnan , Daniel A. Erlanson , Raymond V. Fucini , Derek Bone , Jeffrey S. Iwig , Luis Acosta , Ashley Untereiner , Asmita Pant , Avalon Patton , Leyla L. Sanchez-Sanchez , Jian Luo , Stig K. Hansen
Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5–7.5 mg] or 4 once-weekly doses [5–12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was −4.7% to −8.0% across CT-388 doses vs −0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes.
{"title":"Effects of CT-388, a once-weekly signaling-biased dual GLP-1/GIP receptor agonist, on weight loss and glycemic control in preclinical models and participants with obesity","authors":"Manu V. Chakravarthy , Ruben Rodriguez , Anne Hergarden , Michael A. Elliott , Juan P. Frias , Federico A. Argüelles-Tello , Edgar Tenorio , Jonathan E. Rankin , Jingtao Wu , Shyam Krishnan , Daniel A. Erlanson , Raymond V. Fucini , Derek Bone , Jeffrey S. Iwig , Luis Acosta , Ashley Untereiner , Asmita Pant , Avalon Patton , Leyla L. Sanchez-Sanchez , Jian Luo , Stig K. Hansen","doi":"10.1016/j.molmet.2025.102291","DOIUrl":"10.1016/j.molmet.2025.102291","url":null,"abstract":"<div><div>Biased agonism of the glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide receptors (GLP-1R/GIPR) yields greater weight loss and better glycemic control than unbiased agonism in preclinical models. To evaluate whether biased agonism translates into improved efficacy for weight loss and glycemic control in clinical settings, we developed and characterized CT-388, a unimolecular peptide-based dual GLP-1R/GIPR agonist that is cAMP signal-biased at both receptors. In cell-based assays, CT-388 activated GLP-1R and GIPR with both having minimal receptor internalization vs their native ligands. CT-388 improved glycemic control in mice and monkeys, and reduced bodyweight, suppressed appetite, and improved metabolic dysfunction-associated steatohepatitis pathology in mice. In a phase 1, double-blind, randomized, placebo-controlled clinical study (NCT04838405) of CT-388 (subcutaneously administered single doses [0.5–7.5 mg] or 4 once-weekly doses [5–12 mg]) in otherwise healthy participants with overweight or obesity, CT-388 was generally well tolerated with a safety profile consistent with other incretin-based therapies; most treatment-emergent adverse events were mild or moderate. Glycemic parameters were improved during fasting conditions and an oral glucose tolerance test. The mean percent change in bodyweight from baseline to day 29 was −4.7% to −8.0% across CT-388 doses vs −0.5% with placebo. CT-388 pharmacokinetics supported once-weekly dosing. In conclusion, CT-388 demonstrated strong translatability from preclinical to clinical studies with consistent pharmacokinetics and pharmacodynamics across multiple species. In clinical settings, 4 weeks of CT-388 treatment produced clinically meaningful weight loss and improved glycemic control with favorable tolerability. These findings warrant further clinical evaluation of CT-388 for treating obesity and type 2 diabetes.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102291"},"PeriodicalIF":6.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145649092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1016/j.molmet.2025.102285
Manoj K. Gupta , Dario F. De Jesus , Sevim Kahraman , Ivan A. Valdez , Farnaz Shamsi , Lian Yi , Adam C. Swensen , Yu-Hua Tseng , Wei-Jun Qian , Rohit N. Kulkarni
{"title":"Corrigendum to “Insulin receptor-mediated signaling regulates pluripotency markers and lineage differentiation” [Mol Metab 18 (2018) 153–163]","authors":"Manoj K. Gupta , Dario F. De Jesus , Sevim Kahraman , Ivan A. Valdez , Farnaz Shamsi , Lian Yi , Adam C. Swensen , Yu-Hua Tseng , Wei-Jun Qian , Rohit N. Kulkarni","doi":"10.1016/j.molmet.2025.102285","DOIUrl":"10.1016/j.molmet.2025.102285","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102285"},"PeriodicalIF":6.6,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145596873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1016/j.molmet.2025.102290
Yang Chen , Lin Liu , Ryan P. Calhoun , Lan Cheng , David Steger , Patrick Seale
Objective
Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.
Methods
We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. In vivo relevance was tested using adipocyte precursor–selective Cux1 knockout and lineage reporter mice.
Results
Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including PPARG in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. Cux1 deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. In vivo, Cux1 deletion in APCs of mice increased de novo adipocyte formation during early stages of obesity development.
Conclusions
The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,
{"title":"The transcription factor CUX1 exerts opposing roles in human and mouse adipocyte differentiation","authors":"Yang Chen , Lin Liu , Ryan P. Calhoun , Lan Cheng , David Steger , Patrick Seale","doi":"10.1016/j.molmet.2025.102290","DOIUrl":"10.1016/j.molmet.2025.102290","url":null,"abstract":"<div><h3>Objective</h3><div>Adipocyte differentiation is critical for the metabolically protective expansion of adipose tissue. Impaired differentiation drives lipodystrophy and pathologic tissue remodeling, major contributors to cardiometabolic diseases. The differentiation process is governed by master transcription factors, including the pioneer factor C/EBPβ, which initiates the adipogenic program. Here, we sought to identify novel C/EBPβ-associated factors that regulate human adipocyte differentiation.</div></div><div><h3>Methods</h3><div>We used chromatin immunoprecipitation followed by selective isolation of chromatin-associated proteins (ChIP-SICAP) to identify proteins that interact with C/EBPβ on chromatin during human adipocyte differentiation. Candidate factors were assessed for their effects on differentiation, through conducting a CRISPR/Cas9-based knockout screen in human adipocyte precursor cells (hAPCs). The transcription factor CUX1 emerged as a top candidate. We performed gain- and loss-of-function studies in primary human and mouse adipocyte differentiation models, coupled with RNA-seq and ChIP-seq, to define CUX1-regulated genes and pathways. <em>In vivo</em> relevance was tested using adipocyte precursor–selective <em>Cux1</em> knockout and lineage reporter mice.</div></div><div><h3>Results</h3><div>Loss of CUX1 impaired, whereas its overexpression enhanced, adipocyte differentiation in hAPCs. RNA-seq and ChIP-seq analyses revealed that CUX1 promotes the expression of key adipogenic genes, including <em>PPARG</em> in hAPCs. By contrast, CUX1 exerted the opposite effect in mouse adipocyte differentiation. <em>Cux1</em> deletion enhanced, while CUX1 overexpression suppressed, differentiation in mouse APCs (mAPCs). CUX1 exhibited distinct chromatin-binding patterns and motif enrichment profiles in mouse versus human cells. <em>In vivo</em>, <em>Cux1</em> deletion in APCs of mice increased <em>de novo</em> adipocyte formation during early stages of obesity development.</div></div><div><h3>Conclusions</h3><div>The transcription factor CUX1 regulates adipocyte differentiation in opposite directions in humans and mice, emphasizing the need for species-specific models in metabolic disease research,</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102290"},"PeriodicalIF":6.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1016/j.molmet.2025.102284
Gabriel Brawerman , Jasmine Pipella , Peter J. Thompson
{"title":"Corrigendum to “DNA damage to β cells in culture recapitulates features of senescent β cells that accumulate in type 1 diabetes” [Mol Metabol 62 (2022) 101524]","authors":"Gabriel Brawerman , Jasmine Pipella , Peter J. Thompson","doi":"10.1016/j.molmet.2025.102284","DOIUrl":"10.1016/j.molmet.2025.102284","url":null,"abstract":"","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102284"},"PeriodicalIF":6.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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.molmet.2025.102289
Koy Min Chue , Sunny Hei Wong , Tao Zuo , Yusuf Ali
The epidemic of obesity and metabolic syndrome is a major public health concern internationally. There is increasing knowledge and research in areas of appetite regulation and drivers of obesity but there is still a gap on how the interactomes are altered in a metabolically dysregulated human body. The human microbiome has been implicated in the pathogenesis of obesity. While the association of gut bacteriome dysbiosis is well described in obesity and metabolic syndrome, there is a lack of an integrative understanding about the roles of the non-bacterial microbiome (virome, mycobiome, and archaeome) in the pathogenesis and protection of obesity and metabolic syndrome. Accumulating studies have revealed that the non-bacterial microbes in the gut, including viruses/phages, fungi, and archaea, are profoundly altered in obesity, and impact host adiposity and physiology in nuanced manners. In this review, we aim to provide a comprehensive view on the role and the mechanisms of the gut virome, mycobiome, and archaeome in obesity. These insights will shed light on the translational value as well as the future research directions for harnessing the gut non-bacterial microbial entities in the therapeutics and prevention of metabolic diseases.
{"title":"The role of the gut non-bacterial microbiome (virome, mycobiome, archaeome) and its impact on obesity","authors":"Koy Min Chue , Sunny Hei Wong , Tao Zuo , Yusuf Ali","doi":"10.1016/j.molmet.2025.102289","DOIUrl":"10.1016/j.molmet.2025.102289","url":null,"abstract":"<div><div>The epidemic of obesity and metabolic syndrome is a major public health concern internationally. There is increasing knowledge and research in areas of appetite regulation and drivers of obesity but there is still a gap on how the interactomes are altered in a metabolically dysregulated human body. The human microbiome has been implicated in the pathogenesis of obesity. While the association of gut bacteriome dysbiosis is well described in obesity and metabolic syndrome, there is a lack of an integrative understanding about the roles of the non-bacterial microbiome (virome, mycobiome, and archaeome) in the pathogenesis and protection of obesity and metabolic syndrome. Accumulating studies have revealed that the non-bacterial microbes in the gut, including viruses/phages, fungi, and archaea, are profoundly altered in obesity, and impact host adiposity and physiology in nuanced manners. In this review, we aim to provide a comprehensive view on the role and the mechanisms of the gut virome, mycobiome, and archaeome in obesity. These insights will shed light on the translational value as well as the future research directions for harnessing the gut non-bacterial microbial entities in the therapeutics and prevention of metabolic diseases.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102289"},"PeriodicalIF":6.6,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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.molmet.2025.102288
Orion S. Willoughby , Anna S. Nichenko , Matthew H. Brisendine , Niloufar Amiri , Shelby N. Henry , Daniel S. Braxton , John R. Brown , Braeden J. Kraft , Kalyn S. Jenkins , Adele K. Addington , Alexey V. Zaitsev , Steven T. Burrows , Ryan P. McMillan , Haiyan Zhang , Spencer A. Tye , Charles P. Najt , Siobhan E. Craige , Timothy W. Rhoads , Junco S. Warren , Joshua C. Drake
Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.
{"title":"Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism","authors":"Orion S. Willoughby , Anna S. Nichenko , Matthew H. Brisendine , Niloufar Amiri , Shelby N. Henry , Daniel S. Braxton , John R. Brown , Braeden J. Kraft , Kalyn S. Jenkins , Adele K. Addington , Alexey V. Zaitsev , Steven T. Burrows , Ryan P. McMillan , Haiyan Zhang , Spencer A. Tye , Charles P. Najt , Siobhan E. Craige , Timothy W. Rhoads , Junco S. Warren , Joshua C. Drake","doi":"10.1016/j.molmet.2025.102288","DOIUrl":"10.1016/j.molmet.2025.102288","url":null,"abstract":"<div><div>Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.</div></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"103 ","pages":"Article 102288"},"PeriodicalIF":6.6,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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