Pub Date : 2025-10-24DOI: 10.1016/j.metabol.2025.156424
Guanghong Jia , Christos S. Mantzoros , Michael A. Hill
{"title":"Inter-organ crosstalk in health and cardiovascular-renal-hepatic-metabolic disease: A multidisciplinary perspective","authors":"Guanghong Jia , Christos S. Mantzoros , Michael A. Hill","doi":"10.1016/j.metabol.2025.156424","DOIUrl":"10.1016/j.metabol.2025.156424","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156424"},"PeriodicalIF":11.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145417358","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}
Classical biomarkers of diabetic kidney disease (DKD), including serum creatinine and albuminuria, cannot detect the disease in early stages, leading to worsened complications. This study aimed to introduce a panel of early diagnostic biomarkers for DKD through meta-analysis of longitudinal metabolomics studies.
Methods
A systematic search was conducted across PubMed, Web of Science, and Scopus up to May 12, 2025. Only studies were included in which urine or blood samples were collected from individuals with diabetes and the participants were followed over time. The outcomes were defined as DKD incidence, albuminuria progression, rapid estimated glomerular filtration rate decline, end-stage renal disease, or all-cause mortality. Relative ratio (95 % confidence intervals (CI)) or correlation coefficients (95 % CI) of baseline metabolites with these outcomes were extracted from the included studies.
Results
The analysis included 39 studies covering 52 populations, with a total sample size of 31,012 individuals. The meta-analysis incorporated 170 blood and 12 urine metabolites, of which 65 and 11 showed significant associations with the outcomes, respectively. Enrichment analyses of the differential metabolites highlighted the reprogramming of amino acid, lipid, and energy metabolism.
Conclusion
This meta-analysis introduces metabolic biomarkers strongly associated with DKD incidence or progression. Furthermore, this study underscores the rewiring of metabolic pathways related to energy homeostasis as an adaptation to the prolonged insults of diabetic milieu. The limitations of this study are, the variation in multivariable adjustment methods used across the included studies and the lack of established decision thresholds for the proposed biomarkers.
糖尿病肾病（DKD）的经典生物标志物，包括血清肌酐和蛋白尿，不能在早期发现疾病，导致并发症恶化。本研究旨在通过纵向代谢组学研究的荟萃分析，介绍一组DKD的早期诊断生物标志物。方法系统检索截至2025年5月12日的PubMed、Web of Science和Scopus。只有从糖尿病患者身上收集尿液或血液样本，并对参与者进行长期随访的研究才被纳入其中。结果定义为DKD发生率、蛋白尿进展、肾小球滤过率快速下降、终末期肾病或全因死亡率。从纳入的研究中提取基线代谢物与这些结果的相对比率（95%置信区间（CI））或相关系数（95% CI）。结果该分析包括39项研究，涵盖52个人群，总样本量为31,012人。荟萃分析纳入了170种血液代谢物和12种尿液代谢物，其中65种和11种分别显示与结果显著相关。对差异代谢物的富集分析强调了氨基酸、脂质和能量代谢的重编程。该荟萃分析引入了与DKD发病率或进展密切相关的代谢生物标志物。此外，这项研究强调了与能量稳态相关的代谢途径的重新布线，作为对糖尿病环境长期损害的适应。本研究的局限性是，在纳入的研究中使用的多变量调整方法存在差异，并且缺乏所提议的生物标志物的既定决策阈值。
{"title":"Metabolomics analysis of diabetic kidney disease for discovering early diagnostic biomarkers: A systematic review and meta-analysis of prospective studies","authors":"Zahra Ramazani , Rezvan Adibi , Alieh Gholaminejad , Marjan Mansourian , Yousof Gheisari","doi":"10.1016/j.metabol.2025.156422","DOIUrl":"10.1016/j.metabol.2025.156422","url":null,"abstract":"<div><h3>Background</h3><div>Classical biomarkers of diabetic kidney disease (DKD), including serum creatinine and albuminuria, cannot detect the disease in early stages, leading to worsened complications. This study aimed to introduce a panel of early diagnostic biomarkers for DKD through meta-analysis of longitudinal metabolomics studies.</div></div><div><h3>Methods</h3><div>A systematic search was conducted across PubMed, Web of Science, and Scopus up to May 12, 2025. Only studies were included in which urine or blood samples were collected from individuals with diabetes and the participants were followed over time. The outcomes were defined as DKD incidence, albuminuria progression, rapid estimated glomerular filtration rate decline, end-stage renal disease, or all-cause mortality. Relative ratio (95 % confidence intervals (CI)) or correlation coefficients (95 % CI) of baseline metabolites with these outcomes were extracted from the included studies.</div></div><div><h3>Results</h3><div>The analysis included 39 studies covering 52 populations, with a total sample size of 31,012 individuals. The meta-analysis incorporated 170 blood and 12 urine metabolites, of which 65 and 11 showed significant associations with the outcomes, respectively. Enrichment analyses of the differential metabolites highlighted the reprogramming of amino acid, lipid, and energy metabolism.</div></div><div><h3>Conclusion</h3><div>This meta-analysis introduces metabolic biomarkers strongly associated with DKD incidence or progression. Furthermore, this study underscores the rewiring of metabolic pathways related to energy homeostasis as an adaptation to the prolonged insults of diabetic milieu. The limitations of this study are, the variation in multivariable adjustment methods used across the included studies and the lack of established decision thresholds for the proposed biomarkers.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156422"},"PeriodicalIF":11.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516604","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 : 2025-10-24DOI: 10.1016/j.metabol.2025.156421
Xue You , Qian Peng , Wenju Qian , Zhiqin Xie , Yijun Lin , Yikuo Gai , Jingran Ye , Ying Feng
Background
β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function.
Methods
Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis.
Results
SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression.
Conclusions
SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.
{"title":"SRSF1 is essential for pancreatic β-cell proliferation and the maintenance of glucose homeostasis in mice","authors":"Xue You , Qian Peng , Wenju Qian , Zhiqin Xie , Yijun Lin , Yikuo Gai , Jingran Ye , Ying Feng","doi":"10.1016/j.metabol.2025.156421","DOIUrl":"10.1016/j.metabol.2025.156421","url":null,"abstract":"<div><h3>Background</h3><div>β-Cell proliferation is vital for adapting to metabolic stress. Failure to expand β-cell mass during insulin resistance and aging contributes to dysfunction and diabetes. Understanding the mechanisms behind β-cell proliferation issues and dysfunction is crucial. SRSF1 is a central regulator of cell proliferation and survival, but its influence on β-cell proliferation and glucose control remains unclear. This study aims to investigate the role of SRSF1 in β-cell proliferation and its impact on glucose regulation. By examining the consequences of SRSF1 deficiency in pancreatic β-cells, we seek to elucidate the mechanisms linking SRSF1 to β-cell maintenance and function.</div></div><div><h3>Methods</h3><div>Mice with pancreatic β-cell-specific deletion of SRSF1 and a Rosa26-tdT lineage reporter were generated. Pancreatic sections were analyzed using immunostaining for insulin, glucagon, somatostatin, Ki67, tdT, proinsulin, TUNEL, and ER stress markers, as well as HE staining. Glucose tolerance tests, glucose and insulin measurements were performed in knockout and control mice. RNA-seq analyzed gene expression changes in 4-month-old islets, while scRNA-seq assessed cellular heterogeneity and gene expression profiles in 10-month-old mice islets. Knockdown assays and puromycin labeling experiments measured new protein synthesis.</div></div><div><h3>Results</h3><div>SRSF1 deficiency resulted in glucose intolerance and impaired insulin secretion, worsening with age. At early stages, knockout islets exhibited reduced β-cell proliferation accompanied by compensatory α-cell expansion. By 4 months, RNA-seq analysis showed downregulation of ribosome biogenesis and cell cycle genes, along with upregulation of α-cell determinants and progenitor-associated factors. Histological examination further revealed a decreased β-cell fraction, an increased α-cell fraction, and a small subset of α-cells co-expressing somatostatin, indicative of transient, stress-associated phenotypic plasticity. scRNA-seq identified ER stress and altered β-cell fate in knockout β-cells from 10-month-old mice. Notably, these changes were absent in 4-month-old knockout islets, indicating ER stress as a secondary response to proliferative defects from SRSF1 deficiency. Mechanistically, SRSF1 employs mechanisms similar to MYC to promote β-cell proliferation, with its effects on β-cells through the regulation of MYC expression.</div></div><div><h3>Conclusions</h3><div>SRSF1 is essential for β-cell proliferation and function through MYC-mediated pathways. Its deficiency disrupts β-cell homeostasis and contributes to metabolic dysfunction in mice, underscoring its importance in preserving functional β-cells and maintaining glucose balance.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156421"},"PeriodicalIF":11.9,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145370426","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 : 2025-10-17DOI: 10.1016/j.metabol.2025.156418
Limeng Pan , Yi He , Yuxi Xiang , Beibei Mao , Xiaoyu Meng , Yaming Guo , Zhihan Wang , Ranran Kan , Siyi Wang , Xuhang Shen , Tianrong Pan , Zhelong Liu , Junhui Xie , Yan Yang , Danpei Li , Xuefeng Yu
Background and aims
Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression.
Methods
The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific Angptl8 knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. In vitro, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor in vitro and proximal tubule-specific Akt2 knockout mice in vivo.
Results
ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific Angptl8 knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. In vitro, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects in vitro and in vivo.
Conclusions
Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.
{"title":"Angiopoietin-like protein 8 mediates inflammation and fibrosis of tubular cells in diabetic kidney disease progression by interacting with Akt2","authors":"Limeng Pan , Yi He , Yuxi Xiang , Beibei Mao , Xiaoyu Meng , Yaming Guo , Zhihan Wang , Ranran Kan , Siyi Wang , Xuhang Shen , Tianrong Pan , Zhelong Liu , Junhui Xie , Yan Yang , Danpei Li , Xuefeng Yu","doi":"10.1016/j.metabol.2025.156418","DOIUrl":"10.1016/j.metabol.2025.156418","url":null,"abstract":"<div><h3>Background and aims</h3><div>Angiopoietin-like protein 8 (ANGPTL8), an important regulator of glucose and lipid metabolism, has recently been shown to be associated with renal function decline in patients with diabetic kidney disease (DKD). However, the underlying molecular mechanisms remain unclear. This study aimed to elucidate the novel role of ANGPTL8 in DKD progression.</div></div><div><h3>Methods</h3><div>The renal expression of ANGPTL8 was measured in patients and murine models with DKD. Proximal tubule-specific <em>Angptl8</em> knockout mice were generated to elucidate the role of ANGPTL8 in the pathogenesis of DKD. <em>In vitro</em>, ANGPTL8 was inhibited in human proximal tubular epithelial cells (PTECs) under high glucose plus palmitic acid (HGPA) stress. ANGPTL8 interacting proteins were screened using the human proteome microarray and validated by complementary interaction assays. Functional validation employed the Akt2 small interfering RNA and the specific Akt2 inhibitor <em>in vitro</em> and proximal tubule-specific <em>Akt2</em> knockout mice <em>in vivo</em>.</div></div><div><h3>Results</h3><div>ANGPTL8 expression was significantly increased in renal proximal tubules during DKD. Proximal tubule-specific <em>Angptl8</em> knockout ameliorated tubular injury and reduced tubular inflammation and fibrosis in DKD mice. <em>In vitro</em>, ANGPTL8 inhibition protected human PTECs against HGPA-induced inflammation and epithelial-mesenchymal transition (EMT). Mechanistically, intracellular ANGPTL8 directly binds to and activates Akt2, triggering downstream NF-κB pathway activation and GSK3β inhibition. Akt2 inhibition abolished ANGPTL8's pathogenic effects <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate for the first time that elevated tubular ANGPTL8 promotes tubular inflammation and fibrosis during DKD by interacting with Akt2, highlighting the ANGPTL8-Akt2 axis as a promising target to prevent DKD progression.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156418"},"PeriodicalIF":11.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329578","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}
β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.
{"title":"Pancreas meets brain: β-hydroxybutyrate as a novel “β-cellular” metabolism therapy","authors":"Caroline Lopa , Donatella Pietrangelo , Gaetano Santulli , Jessica Gambardella , Speranza Rubattu , Mihaela Stefan-Lifshitz , Crystal Nieves Garcia , Stanislovas S. Jankauskas , Angela Lombardi","doi":"10.1016/j.metabol.2025.156419","DOIUrl":"10.1016/j.metabol.2025.156419","url":null,"abstract":"<div><div>β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156419"},"PeriodicalIF":11.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318588","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 : 2025-10-14DOI: 10.1016/j.metabol.2025.156420
Jiang Du , Yujie Li , Xinxing Zhu , Jingwen Gao , Yuxuan Zhang , Chiheng Wang , Di Han , Liang Qiao , Beilin Kou , Rui Guo , Hongen Zhang , Juntang Lin
Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this study, we found that methyltransferase-like 1 (METTL1) is upregulated in the livers of both MASLD mice and clinical samples. Hepatocyte-specific depletion of METTL1 inhibits lipid synthesis and promotes lipid oxidation, alleviating metabolic disorders in high-fat diet (HFD)-induced MASLD mice. Conversely, overexpression of METTL1 enhances lipid synthesis while suppressing lipid oxidation. Mechanistically, METTL1 regulates the stability and protein expression levels of FoxO1 mRNA by methylating the Exon1 region of FoxO1, as demonstrated by m7G sequencing. Additionally, we found that overexpression of FoxO1 counteracts the protective effects of METTL1 deficiency on metabolic disorders in MASLD mice. Moreover, we identified a potent small-molecule inhibitor of METTL1, specifically Homatropine Methylbromide (HtMBm), which significantly ameliorated HFD-induced MASLD. Overall, our study suggests that METTL1 plays a crucial role in the progression of MASLD and highlights the therapeutic potential of targeting METTL1 to modulate fatty acid metabolism in this condition.
{"title":"METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease","authors":"Jiang Du , Yujie Li , Xinxing Zhu , Jingwen Gao , Yuxuan Zhang , Chiheng Wang , Di Han , Liang Qiao , Beilin Kou , Rui Guo , Hongen Zhang , Juntang Lin","doi":"10.1016/j.metabol.2025.156420","DOIUrl":"10.1016/j.metabol.2025.156420","url":null,"abstract":"<div><div>Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this study, we found that methyltransferase-like 1 (METTL1) is upregulated in the livers of both MASLD mice and clinical samples. Hepatocyte-specific depletion of METTL1 inhibits lipid synthesis and promotes lipid oxidation, alleviating metabolic disorders in high-fat diet (HFD)-induced MASLD mice. Conversely, overexpression of METTL1 enhances lipid synthesis while suppressing lipid oxidation. Mechanistically, METTL1 regulates the stability and protein expression levels of FoxO1 mRNA by methylating the Exon1 region of FoxO1, as demonstrated by m7G sequencing. Additionally, we found that overexpression of FoxO1 counteracts the protective effects of METTL1 deficiency on metabolic disorders in MASLD mice. Moreover, we identified a potent small-molecule inhibitor of METTL1, specifically Homatropine Methylbromide (HtMBm), which significantly ameliorated HFD-induced MASLD. Overall, our study suggests that METTL1 plays a crucial role in the progression of MASLD and highlights the therapeutic potential of targeting METTL1 to modulate fatty acid metabolism in this condition.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156420"},"PeriodicalIF":11.9,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308571","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 : 2025-10-13DOI: 10.1016/j.metabol.2025.156414
Emily F. Ashlaw , Clinton T. Elfers , Kylie S. Chichura , Isabella Chavez Miranda , Aelish McGivney , Oleg G. Chepurny , George G. Holz , Ginger Mullins , Laura J. den Hartigh , Yongjun Liu , Christian L. Roth , Robert P. Doyle
Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.
{"title":"A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity","authors":"Emily F. Ashlaw , Clinton T. Elfers , Kylie S. Chichura , Isabella Chavez Miranda , Aelish McGivney , Oleg G. Chepurny , George G. Holz , Ginger Mullins , Laura J. den Hartigh , Yongjun Liu , Christian L. Roth , Robert P. Doyle","doi":"10.1016/j.metabol.2025.156414","DOIUrl":"10.1016/j.metabol.2025.156414","url":null,"abstract":"<div><div>Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156414"},"PeriodicalIF":11.9,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145301916","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 : 2025-10-10DOI: 10.1016/j.metabol.2025.156415
Nawarat Rattanajearakul , Kunio Kondoh , Ou Fu , Shiki Okamoto , Kenta Kobayashi , Ken-ichiro Nakajima , Yasuhiko Minokoshi
Background
Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.
Methods
Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-d-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH.
Results
Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK–regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection.
Conclusion
Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.
{"title":"Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus","authors":"Nawarat Rattanajearakul , Kunio Kondoh , Ou Fu , Shiki Okamoto , Kenta Kobayashi , Ken-ichiro Nakajima , Yasuhiko Minokoshi","doi":"10.1016/j.metabol.2025.156415","DOIUrl":"10.1016/j.metabol.2025.156415","url":null,"abstract":"<div><h3>Background</h3><div>Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.</div></div><div><h3>Methods</h3><div>Male mice were subjected to glucoprivation through the intraperitoneal (i.p.) administration of 2-deoxy-<span>d</span>-glucose (2DG) and were examined for food selection between a high-carbohydrate diet (HCD) and a high-fat diet (HFD) in a diet choice paradigm. This involved the chemogenetic or optogenetic modulation of the neural activity of AMP-activated protein kinase (AMPK)-regulated corticotropin-releasing hormone (CRH) neurons, melanocortin-4 receptor (MC4R) neurons in the paraventricular nucleus of the hypothalamus (PVH), and neuropeptide Y (NPY) neurons projecting to the PVH.</div></div><div><h3>Results</h3><div>Glucoprivation induced by 2DG administration in mice influenced two distinct neural pathways in the PVH that separately promote the intake of an HCD or an HFD. Injection of 2DG activated PVH-projecting NPY neurons in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), resulting in a rapid increase in HCD intake through stimulation of PVH AMPK–regulated CRH neurons and recovery from glucoprivation. In contrast, PVH-projecting NPY neurons in the NTS, VLM, and arcuate nucleus of the hypothalamus (ARC) promoted HFD intake by inhibiting MC4R neurons in the PVH, reflecting the strong innate preference for an HFD in mice. The ARC NPY neurons specifically promoted HFD selection.</div></div><div><h3>Conclusion</h3><div>Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156415"},"PeriodicalIF":11.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280693","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 : 2025-10-10DOI: 10.1016/j.metabol.2025.156416
Yuan Qiao , Yijia Zhang , Cuiting Sun , Qi Jin , Peng Qu , Zecheng Li , Yang Qiu , Hua Meng , Dantao Peng , Liang Peng
Objectives
Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain largely undefined. Emerging evidence implicates epigenetic regulators in modulating autophagic pathways in metabolic diseases. Therefore, this study aimed to elucidate the role of a histone methyltransferase, nuclear receptor binding SET domain protein 2 (NSD2), in regulating autophagy and its contribution to MASLD progression.
Methods
NSD2 expression levels were evaluated in liver tissues from patients with MASLD and mouse models. Functional studies were conducted using hepatocyte-specific Nsd2 knockout and overexpression mouse models, along with cleavage under targets and tagmentation analysis in hepatocyte cell lines. Additionally, the effects of pharmacological NSD2 inhibition using NSC663284 were evaluated in human liver organoids. Autophagy, hepatic steatosis, and related epigenetic changes were assessed through molecular and histological techniques.
Results
NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity. Hepatic NSD2 deficiency alleviated diet-induced autophagy impairment and steatosis, while NSD2 overexpression exacerbated these pathologies. Mechanistically, NSD2 epigenetically suppressed TFEB transcription by promoting trimethylation of histone H4 at lysine 20, impairing autophagy. Pharmacological inhibition of NSD2 with NSC663284 similarly alleviated hepatic steatosis in human liver organoids.
Conclusion
NSD2 acts as a key epigenetic suppressor of TFEB-mediated autophagy in the liver, promoting lipid accumulation and MASLD progression. Targeting NSD2 represents a promising therapeutic strategy for MASLD.
{"title":"NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway","authors":"Yuan Qiao , Yijia Zhang , Cuiting Sun , Qi Jin , Peng Qu , Zecheng Li , Yang Qiu , Hua Meng , Dantao Peng , Liang Peng","doi":"10.1016/j.metabol.2025.156416","DOIUrl":"10.1016/j.metabol.2025.156416","url":null,"abstract":"<div><h3>Objectives</h3><div>Impaired autophagy is increasingly recognized as a key contributor to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). However, its underlying molecular mechanisms remain largely undefined. Emerging evidence implicates epigenetic regulators in modulating autophagic pathways in metabolic diseases. Therefore, this study aimed to elucidate the role of a histone methyltransferase, nuclear receptor binding SET domain protein 2 (NSD2), in regulating autophagy and its contribution to MASLD progression.</div></div><div><h3>Methods</h3><div>NSD2 expression levels were evaluated in liver tissues from patients with MASLD and mouse models. Functional studies were conducted using hepatocyte-specific <em>Nsd2</em> knockout and overexpression mouse models, along with cleavage under targets and tagmentation analysis in hepatocyte cell lines. Additionally, the effects of pharmacological NSD2 inhibition using NSC663284 were evaluated in human liver organoids. Autophagy, hepatic steatosis, and related epigenetic changes were assessed through molecular and histological techniques.</div></div><div><h3>Results</h3><div>NSD2 expression was markedly elevated in both patient livers and murine models, correlating positively with disease severity. Hepatic NSD2 deficiency alleviated diet-induced autophagy impairment and steatosis, while NSD2 overexpression exacerbated these pathologies. Mechanistically, NSD2 epigenetically suppressed TFEB transcription by promoting trimethylation of histone H4 at lysine 20, impairing autophagy. Pharmacological inhibition of NSD2 with NSC663284 similarly alleviated hepatic steatosis in human liver organoids.</div></div><div><h3>Conclusion</h3><div>NSD2 acts as a key epigenetic suppressor of TFEB-mediated autophagy in the liver, promoting lipid accumulation and MASLD progression. Targeting NSD2 represents a promising therapeutic strategy for MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156416"},"PeriodicalIF":11.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275315","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 : 2025-10-09DOI: 10.1016/j.metabol.2025.156417
Linyi Li , Yu Wang , Zhiyong Du , Huahui Yu , Yunyun Yang , Zihan Zhang , Yanru Duan , Lijie Han , Chaowei Hu , Yunhui Du , Haili Sun , Xuechun Sun , Jingci Xing , Xiaoqian Gao , Dong Chen , Yuhui Wang , Xinwei Hua , Jianping Li , Yanwen Qin
Background and aims
Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain incompletely understood. Cytosolic citrate plays a crucial role in DNL, with aconitase 1 (ACO1), a key enzyme in citrate metabolism, potentially influencing lipid metabolism. The aim of this study was to clarify the role of hepatic ACO1 in regulating both hepatic and systemic lipid homeostasis.
Methods
ACO1 expression and activity were assessed in liver tissues from multiple hypercholesterolemic animal models. Using liver-specific genetic manipulation, we examined the effects of hepatic ACO1 knockout and overexpression on hypercholesterolemia and atherosclerosis. Targeted metabolomics and stable isotope-based flux analysis were used to profile hepatic substrate utilization patterns.
Results
Hepatic ACO1 expression was significantly reduced in both hypercholesterolemic patients and animal models. Hepatocyte-specific ACO1 deletion exacerbated dyslipidemia, while ACO1 overexpression improved hypercholesterolemia, hepatic steatosis, and atherosclerosis in mouse models. Mechanistically, ACO1 overexpression redirected cytosolic citrate metabolism toward α-ketoglutarate, thereby limiting acetyl-CoA availability for DNL and suppressing fatty acid and cholesterol synthesis. These lipid-lowering effects were dependent on ACO1 enzymatic activity, as catalytically inactive ACO1 mutants failed to replicate the observed benefits.
Conclusion
Our findings identify hepatic ACO1 as a critical regulator of lipid metabolism homeostasis. Promoting ACO1-mediated citrate redirection effectively mitigates hypercholesterolemia and atherosclerosis by suppressing hepatic DNL, highlighting ACO1 as a potential target for lipid-lowering therapies.
{"title":"Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia","authors":"Linyi Li , Yu Wang , Zhiyong Du , Huahui Yu , Yunyun Yang , Zihan Zhang , Yanru Duan , Lijie Han , Chaowei Hu , Yunhui Du , Haili Sun , Xuechun Sun , Jingci Xing , Xiaoqian Gao , Dong Chen , Yuhui Wang , Xinwei Hua , Jianping Li , Yanwen Qin","doi":"10.1016/j.metabol.2025.156417","DOIUrl":"10.1016/j.metabol.2025.156417","url":null,"abstract":"<div><h3>Background and aims</h3><div>Targeting key enzymes in hepatic de novo lipogenesis (DNL) presents a promising strategy for treating hypercholesterolemia. However, the precise regulatory mechanisms governing hepatic DNL remain incompletely understood. Cytosolic citrate plays a crucial role in DNL, with aconitase 1 (ACO1), a key enzyme in citrate metabolism, potentially influencing lipid metabolism. The aim of this study was to clarify the role of hepatic ACO1 in regulating both hepatic and systemic lipid homeostasis.</div></div><div><h3>Methods</h3><div>ACO1 expression and activity were assessed in liver tissues from multiple hypercholesterolemic animal models. Using liver-specific genetic manipulation, we examined the effects of hepatic ACO1 knockout and overexpression on hypercholesterolemia and atherosclerosis. Targeted metabolomics and stable isotope-based flux analysis were used to profile hepatic substrate utilization patterns.</div></div><div><h3>Results</h3><div>Hepatic ACO1 expression was significantly reduced in both hypercholesterolemic patients and animal models. Hepatocyte-specific ACO1 deletion exacerbated dyslipidemia, while ACO1 overexpression improved hypercholesterolemia, hepatic steatosis, and atherosclerosis in mouse models. Mechanistically, ACO1 overexpression redirected cytosolic citrate metabolism toward α-ketoglutarate, thereby limiting acetyl-CoA availability for DNL and suppressing fatty acid and cholesterol synthesis. These lipid-lowering effects were dependent on ACO1 enzymatic activity, as catalytically inactive ACO1 mutants failed to replicate the observed benefits.</div></div><div><h3>Conclusion</h3><div>Our findings identify hepatic ACO1 as a critical regulator of lipid metabolism homeostasis. Promoting ACO1-mediated citrate redirection effectively mitigates hypercholesterolemia and atherosclerosis by suppressing hepatic DNL, highlighting ACO1 as a potential target for lipid-lowering therapies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"174 ","pages":"Article 156417"},"PeriodicalIF":11.9,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258780","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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