Metabolism: clinical and experimental最新文献

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A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity. 多胺代谢在调节肥胖的脂肪组织稳态中的关键作用。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-11-01 Epub Date: 2025-08-05 DOI: 10.1016/j.metabol.2025.156358
Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki
{"title":"A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity.","authors":"Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki","doi":"10.1016/j.metabol.2025.156358","DOIUrl":"10.1016/j.metabol.2025.156358","url":null,"abstract":"<p><strong>Background and aims: </strong>Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology.</p><p><strong>Methods: </strong>We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured.</p><p><strong>Results: </strong>Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2<sup>-/-</sup> APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers.</p><p><strong>Conclusions: </strong>Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156358"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775789","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}
引用次数: 0
Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes. 运动训练增加2型糖尿病患者骨骼肌鞘磷脂酶并影响线粒体质量控制。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-11-01 Epub Date: 2025-08-07 DOI: 10.1016/j.metabol.2025.156361
Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden
{"title":"Exercise training increases skeletal muscle sphingomyelinases and affects mitochondrial quality control in men with type 2 diabetes.","authors":"Mona Hendlinger, Lucia Mastrototaro, Marten Exterkate, Maria Apostolopoulou, Yanislava Karusheva, Geronimo Heilmann, Polina Lipaeva, Klaus Straßburger, Sofiya Gancheva, Sabine Kahl, Michael Roden","doi":"10.1016/j.metabol.2025.156361","DOIUrl":"10.1016/j.metabol.2025.156361","url":null,"abstract":"<p><p>Lipotoxic ceramides (CERs) are implicated in the development of insulin resistance, type 2 diabetes (T2D) and related complications. Exercise training improves insulin sensitivity, potentially via reducing intracellular lipids or enhancing mitochondrial oxidation. Acid sphingomyelinase (ASM), which hydrolyzes sphingomyelin (SM) to CERs, is crucial for muscle repair and development, yet its role in insulin-resistant states and response to exercise remain unclear. We assessed ASM protein and activity, neutral sphingomyelinase (NSM) and sphingolipid species in skeletal muscle of insulin-sensitive (IS, n = 12), insulin-resistant (IR, n = 11) and T2D men (n = 20), before and after a 12-week high-intensity interval training (HIIT). Comprehensive phenotyping comprised hyperinsulinemic-euglycemic clamps, spiroergometry, targeted lipidomics and assessment of markers of mitochondrial quality control. ASM protein was lower at baseline and increased after HIIT only in T2D (p < 0.05), while ASM activity rose across all groups (IS p < 0.01; IR and T2D p < 0.001). HIIT also increased NSM protein in all groups (p < 0.05). Despite lower baseline SM levels in T2D, HIIT led to elevated CERs species in T2D (C16:0, C20:0, C22:0, C24:1, C24:0) and in IR (C16:0, C20:0) (all p < 0.05). Regression analysis suggested that changes in ASM protein and activity relate to changes in mitochondrial fusion and fission as well as AMP-activated protein kinase (AMPK)-mediated mitophagy. In conclusion, HIIT induces expression of both ASM and NSM and alters CER profiles in insulin-resistant skeletal muscle, independently of changes in insulin sensitivity. ASM could therefore rather contribute to exercise-induced mitochondrial remodeling than driving lipotoxicity, warranting further investigation of ASM as a potential target for exercise mimetic therapies.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156361"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144784781","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}
引用次数: 0
Mini-review of the EAT-Lancet planetary health diet and its role in cardiometabolic disease prevention. 关于EAT-Lancet行星健康饮食及其在心脏代谢疾病预防中的作用的综述。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-11-01 Epub Date: 2025-08-06 DOI: 10.1016/j.metabol.2025.156373
Anna Stubbendorff, Suzanne Janzi, Juulia Jukkola, Moa Morency, Shunming Zhang, Yan Borné, Emily Sonestedt
{"title":"Mini-review of the EAT-Lancet planetary health diet and its role in cardiometabolic disease prevention.","authors":"Anna Stubbendorff, Suzanne Janzi, Juulia Jukkola, Moa Morency, Shunming Zhang, Yan Borné, Emily Sonestedt","doi":"10.1016/j.metabol.2025.156373","DOIUrl":"10.1016/j.metabol.2025.156373","url":null,"abstract":"<p><p>Human diets play a crucial role in both human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems introduced the EAT-Lancet planetary health diet, a universal reference diet designed to promote human health while minimizing environmental degradation. It is a predominantly plant-based dietary pattern, rich in whole grains, vegetables, fruits, legumes, and nuts, while low in red meat and added sugars. In this mini-review, we summarize findings from prospective cohorts examining the EAT-Lancet diet in relation to mortality and cardiometabolic outcomes. Higher adherence to this diet was generally associated with lower risk of all-cause mortality, cardiovascular disease, and type 2 diabetes. However, the magnitude of associations varied depending on cohort characteristics, scoring systems, and methodological factors. In addition, adherence to the EAT-Lancet diet was generally low in the studies reviewed. These results suggest potential public health benefits of adopting the EAT-Lancet diet but also highlight the need for harmonized definitions and further research on underlying mechanisms.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156373"},"PeriodicalIF":11.9,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804434","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}
引用次数: 0
Angiopoietin-like protein 8 mediates inflammation and fibrosis of tubular cells in diabetic kidney disease progression by interacting with Akt2. 血管生成素样蛋白8通过与Akt2相互作用介导糖尿病肾病进展中小管细胞的炎症和纤维化。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-10-17 DOI: 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
{"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":"https://doi.org/10.1016/j.metabol.2025.156418","url":null,"abstract":"<p><strong>Background and aims: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"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}
引用次数: 0
Pancreas meets brain: β-hydroxybutyrate as a novel "β-cellular" metabolism therapy. 胰腺与大脑相遇:β-羟基丁酸作为一种新的“β-细胞”代谢疗法。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-10-16 DOI: 10.1016/j.metabol.2025.156419
Caroline Lopa, Donatella Pietrangelo, Gaetano Santulli, Jessica Gambardella, Speranza Rubattu, Mihaela Stefan-Lifshitz, Crystal Nieves Garcia, Stanislovas S Jankauskas, Angela Lombardi
{"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":"https://doi.org/10.1016/j.metabol.2025.156419","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"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}
引用次数: 0
METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease mettl1介导的fox01 m7G甲基化调节代谢功能障碍相关脂肪肝的脂质代谢
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-10-14 DOI: 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
{"title":"METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease","authors":"Jiang Du ,&nbsp;Yujie Li ,&nbsp;Xinxing Zhu ,&nbsp;Jingwen Gao ,&nbsp;Yuxuan Zhang ,&nbsp;Chiheng Wang ,&nbsp;Di Han ,&nbsp;Liang Qiao ,&nbsp;Beilin Kou ,&nbsp;Rui Guo ,&nbsp;Hongen Zhang ,&nbsp;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}
引用次数: 0
A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity. 一种治疗糖尿病和肥胖症的黑素皮质素4和胰高血糖素样肽1受体多重激动剂。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-10-13 DOI: 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
{"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":"https://doi.org/10.1016/j.metabol.2025.156414","url":null,"abstract":"<p><p>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 male and female 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.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"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}
引用次数: 0
Glucoprivation-induced nutrient preference relies on distinct NPY neurons that project to the paraventricular nucleus of the hypothalamus. 葡萄糖活化诱导的营养偏好依赖于投射到下丘脑室旁核的不同NPY神经元。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-10-10 DOI: 10.1016/j.metabol.2025.156415
Nawarat Rattanajearakul, Kunio Kondoh, Ou Fu, Shiki Okamoto, Kenta Kobayashi, Ken-Ichiro Nakajima, Yasuhiko Minokoshi
{"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":"https://doi.org/10.1016/j.metabol.2025.156415","url":null,"abstract":"<p><strong>Background: </strong>Neural pathways related to total calorie intake have been extensively studied. However, it remains unclear how these mechanisms control food selection.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>Our findings reveal a previously unrecognized mechanism for food selection between HCD and HFD during glucoprivation.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"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}
引用次数: 0
NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway NSD2通过抑制tfeb介导的自噬-溶酶体途径加剧代谢功能障碍相关的脂肪变性肝病进展。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-10-10 DOI: 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
{"title":"NSD2 exacerbates metabolic dysfunction-associated steatotic liver disease progression by suppressing TFEB-mediated autophagy-lysosomal pathway","authors":"Yuan Qiao ,&nbsp;Yijia Zhang ,&nbsp;Cuiting Sun ,&nbsp;Qi Jin ,&nbsp;Peng Qu ,&nbsp;Zecheng Li ,&nbsp;Yang Qiu ,&nbsp;Hua Meng ,&nbsp;Dantao Peng ,&nbsp;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}
引用次数: 0
Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia 肝乌头酶1重定向柠檬酸通量抑制脂肪生成和改善高胆固醇血症。
IF 11.9 1区 医学
Metabolism: clinical and experimental Pub Date : 2025-10-09 DOI: 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
{"title":"Hepatic aconitase 1 redirects citrate flux to suppress lipogenesis and ameliorate hypercholesterolemia","authors":"Linyi Li ,&nbsp;Yu Wang ,&nbsp;Zhiyong Du ,&nbsp;Huahui Yu ,&nbsp;Yunyun Yang ,&nbsp;Zihan Zhang ,&nbsp;Yanru Duan ,&nbsp;Lijie Han ,&nbsp;Chaowei Hu ,&nbsp;Yunhui Du ,&nbsp;Haili Sun ,&nbsp;Xuechun Sun ,&nbsp;Jingci Xing ,&nbsp;Xiaoqian Gao ,&nbsp;Dong Chen ,&nbsp;Yuhui Wang ,&nbsp;Xinwei Hua ,&nbsp;Jianping Li ,&nbsp;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}
引用次数: 0
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