Metabolism: clinical and experimental最新文献

{"title":"Multi-omics profiling reveals CKM syndrome severity as a gradient risk factor for cancer: A prospective cohort study.","authors":"Yu Huang, Yiwei Zhang, Yanjun Zhang, Ziliang Ye, Sisi Yang, Xiaoqin Gan, Yiting Wu, Yuanyuan Zhang, Xianhui Qin","doi":"10.1016/j.metabol.2026.156508","DOIUrl":"https://doi.org/10.1016/j.metabol.2026.156508","url":null,"abstract":"<p><strong>Objective: </strong>Cardiovascular-Kidney-Metabolic (CKM) syndrome, a multisystem disorder, has been linked to cardiovascular and metabolic morbidity, but its association with cancer risk remains poorly characterized. This study aimed to examine the relationship between CKM syndrome severity and the incidence of overall cancer and 18 site-specific cancers, and to identify potential mediating plasma protein and metabolite signatures.</p><p><strong>Methods: </strong>We analyzed data from 351,239 participants in the UK Biobank, classified into five CKM syndrome stages (0-4). Plasma proteomic (2923 proteins) and metabolomic (168 metabolites) profiles were analyzed. Cox models evaluated associations, and mediation analyses identified biological mediators.</p><p><strong>Results: </strong>Over a median 13.5-year follow-up, 44,840 incident cancer cases were documented. Advancing CKM stages (0-3) showed a dose-response relationship with increased overall (per one-stage increase: adjusted HR, 1.05; 95%CI, 1.03-1.07) and eleven site-specific cancer risks (e.g., digestive, respiratory, urinary tracts) (per one-stage increase: adjusted HR ranging from 1.06 to 1.46). Stage 4 remained associated with elevated risk, though attenuated versus stage 3. Multi-omics mediation analysis identified 22 proteins and 2 metabolites that partially mediated the association between CKM stages 0-3 and overall cancer risk, implicating immune and metabolic pathways. Functional enrichment analysis further highlighted the PI3K-Akt signaling pathway and inflammatory processes as key mechanistic contributors.</p><p><strong>Conclusions: </strong>CKM syndrome severity is independently associated with increased cancer risk, partially mediated by proteins and metabolites involved in inflammation, proliferation, and lipid metabolism. These findings support CKM staging as a multisystem disorder with significant oncological implications and highlight potential biomarkers for intervention.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156508"},"PeriodicalIF":11.9,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990003","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}

{"title":"Personalizing bariatric metabolic surgery: Predictors of weight-loss success and risk of weight recurrence.","authors":"Simona Panunzi, Sara Russo, Marcello Pompa, Andrea De Gaetano, Ornella Verrastro, Dario Tuccinardi, Caterina Guidone, Lidia Castagneto Gissey, Giovanni Casella, James R Casella Mariolo, Giulia Angelini, Francois Pattou, Silvia Sabatini, Amalia Gastaldelli, Paul W Franks, Ebaa Al Ozairi, Thomas Sparso, Stefan Bornstein, Carel W Le Roux, Geltrude Mingrone","doi":"10.1016/j.metabol.2026.156495","DOIUrl":"https://doi.org/10.1016/j.metabol.2026.156495","url":null,"abstract":"<p><strong>Background: </strong>Bariatric metabolic surgery (Roux-en-Y gastric bypass [RYGB] and sleeve gastrectomy [SG]) effectively treats obesity and type 2 diabetes; however, weight loss varies, necessitating predictive factors.</p><p><strong>Methods: </strong>We analysed 12- and 24-month weight loss data from 811 patients (RYGB or SG). Factor Analysis of Mixed Data and neural network (NN) modelling identified distinct patient phenotypes and predicted weight-loss patterns. A comparative analysis evaluated weight loss and recurrence between the two procedures.</p><p><strong>Findings: </strong>RYGB showed significantly greater weight loss than SG at both 12 (30.3% vs. 25.4%; p < 0.001) and 24 months (26.3% vs. 21.4%; p < 0.001). SG revealed greater variability with bimodal weight loss distributions. Unsupervised clustering of SG patients highligheted three phenotypes: the highest responders were women with favourable metabolic profiles; the lowest responders were mostly men with insulin resistance and diabetes. A NN achieved an overall accuracy of 72.5% in predicting 12-month weight loss from baseline characteristics. In RYGB, clustering was less distinct, though baseline metabolic health influenced weight trajectories. A NN predicted weight recurrence versus sustained loss with 74% accuracy. Poor outcomes were associated with higher baseline glucose, insulin resistance, and dyslipidemia; younger age and absence of diabetes predicted better responses. RYGB was superior to SG, even for metabolic high-risk individuals.</p><p><strong>Interpretation: </strong>Baseline metabolic health predicts weight-loss outcomes and recurrence risk. RYGB offered greater and more consistent mid-term weight loss, especially benefiting metabolically high-risk patients. Procedure choice must be individualized accounting for specific risk profile and potential complications. These results advocate for a precision-medicine approach in bariatric procedure selection.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156495"},"PeriodicalIF":11.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989917","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}

{"title":"Bone inflammation in postmenopausal women with type 2 diabetes or obesity in relation to Wnt signaling and bone strength","authors":"Giulia Leanza ,&nbsp;Malak Faraj ,&nbsp;Francesca Cannata ,&nbsp;Viola Viola ,&nbsp;Niccolò Pellegrini ,&nbsp;Flavia Tramontana ,&nbsp;Claudio Pedone ,&nbsp;Gianluca Vadalà ,&nbsp;Alessandra Piccoli ,&nbsp;Rocky Strollo ,&nbsp;Francesca Zalfa ,&nbsp;Lorenzo Nevi ,&nbsp;Simone Carotti ,&nbsp;Roberto Civitelli ,&nbsp;Mauro Maccarrone ,&nbsp;Rocco Papalia ,&nbsp;Nicola Napoli","doi":"10.1016/j.metabol.2026.156492","DOIUrl":"10.1016/j.metabol.2026.156492","url":null,"abstract":"<div><h3>Background and aim</h3><div>Type 2 diabetes (T2D) and obesity (OB) are associated with chronic inflammation and increased fracture risk. We aimed to study the impact of inflammation and Wnt pathway regulation on bone health in subjects with T2D or OB.</div></div><div><h3>Methods</h3><div>This study involved 63 postmenopausal women (aged ≥65 years) undergoing hip arthroplasty, including 19 with T2D, 17 with OB, and 27 controls (CTRL). We assessed body composition using dual-energy X-ray absorptiometry (DXA), bone microarchitecture with microcomputed tomography (μCT), and bone strength through compression tests. Bone tissue was collected for gene and protein expression analysis, and serum samples were obtained for cytokine measurement.</div></div><div><h3>Results</h3><div>Bone gene expression analysis revealed increased tumor necrosis factor-alpha (<em>TNF-α</em>; <em>p</em> &lt; 0.0001) and reduced adiponectin (<em>ADIPOQ</em>; <em>p</em> = 0.0041) in T2D. Secreted frizzled-related protein 5 (<em>SFRP5</em>) was elevated in both T2D (p &lt; 0.0001), whereas the OB group showed only a trend toward higher expression (<em>p</em> = 0.060) after BMI adjustment. Interleukin-10 (<em>IL10</em>) was reduced in both T2D (<em>p</em> = 0.0005), while in the OB group <em>IL10</em> was not reduced after BMI adjustment. Importantly, the Wnt inhibitor sclerostin (<em>SOST</em>) was elevated in both T2D and OB subjects (<em>p</em> &lt; 0.0001), while wingless-type family member 10B (<em>WNT10B</em>) and lymphoid enhancer-binding factor 1 (<em>LEF1</em>) were reduced in both T2D (<em>WNT10B</em>: <em>p</em> = 0.0070, <em>LEF1</em>: p &lt; 0.0001) and OB (<em>WNT10B</em>: <em>p</em> = 0.0078, <em>LEF1</em>: <em>p</em> = 0.0199), even after BMI adjustment. Protein expression analysis by immunohistochemistry confirmed reduced non-phosphorylated (active) β-catenin in bone tissue of both T2D and OB subjects. Moreover, key inflammatory markers were associated with alterations in Wnt pathway-related genes. Consistently, serum cytokine analysis showed increased inflammation, with higher TNF-α (<em>p</em> = 0.0084) and lower ADIPOQ (<em>p</em> = 0.0402) levels in T2D, and higher interleukin-6 (IL-6; <em>p</em> = 0.0003) in OB compared to CTRL. Finally, serum TNF-α (<em>r</em> = −0.3557, <em>p</em> = 0.0112) and IL-6 (<em>r</em> = −0.3881, <em>p</em> = 0.0194) levels negatively correlated with bone strength.</div></div><div><h3>Conclusions</h3><div>In conclusion, our results suggest that T2D is associated with increased bone inflammation, and Wnt signaling is downregulated in both T2D and obesity. These observations lay the groundwork for future mechanistic studies on bone fragility in metabolic diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156492"},"PeriodicalIF":11.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949007","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}

{"title":"Global glucagon-like peptide-2 receptor activation linked to increased obesity risk in the UK Biobank","authors":"Peter A. Gerlach ,&nbsp;Sarina Gadgaard ,&nbsp;Jakob S. Madsen ,&nbsp;Peter Lindquist ,&nbsp;Javier Sanchez Lorente ,&nbsp;Felix Faas ,&nbsp;Maria B.N. Gabe ,&nbsp;Mette M. Rosenkilde ,&nbsp;Alexander S. Hauser","doi":"10.1016/j.metabol.2025.156489","DOIUrl":"10.1016/j.metabol.2025.156489","url":null,"abstract":"<div><h3>Objective</h3><div>The glucagon-like peptide-2 receptor (GLP-2R) is recognized as a potential target for the treatment of obesity and type 2 diabetes (T2D). Yet, the impact and mechanism of GLP-2R activation on these metabolic traits remain unclear in humans.</div></div><div><h3>Methods</h3><div>We conducted in vitro pharmacological characterization of 30 naturally occurring GLP-2R missense variants identified from the UK Biobank, assessing receptor activity via cyclic adenosine monophosphate (cAMP) production and β-arrestin 2 recruitment. To study the effect of GLP-2R activation on metabolic traits, we categorized variants into functional groups based on their signaling profiles and performed genetic association tests in ∼500,000 UK Biobank participants.</div></div><div><h3>Results</h3><div>We experimentally identified variants with both increased and decreased effects on receptor signaling and computationally identified an additional 34 predicted Loss-of-Function (pLoF) variants. Notably, the most frequent GLP-2R variant, D470N, with an allele frequency of 32% in the UK population, displayed increased cAMP production. Mechanistically, the increased cAMP production of D470N is likely linked to reduced β-arrestin recruitment and reduced internalization. Genetic associations showed that D470N was linked to increased risk of obesity, T2D, and higher Body Mass Index (BMI), body fat, glycated hemoglobin (HbA1c), and diastolic/systolic blood pressure. In contrast, Loss-of-Function (LoF) variants were associated with a decreased risk of obesity and reduced body fat percentage.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that global GLP-2R activation, encompassing the effects across all tissues, is associated with increased risk of obesity. This study highlights the role of the GLP-2R in metabolic diseases, guiding the future development of biased GLP-2R ligands and the potential adverse effects of GLP-2R modulation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156489"},"PeriodicalIF":11.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948973","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}

{"title":"Proteomic effects of short-term liraglutide vs. placebo in a blinded crossover RCT: Implications for efficacy, safety, and comparison with semaglutide","authors":"Konstantinos Stefanakis ,&nbsp;Valeria Gutierrez de Piñeres ,&nbsp;Preethi Veeragandham ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2026.156493","DOIUrl":"10.1016/j.metabol.2026.156493","url":null,"abstract":"<div><h3>Background</h3><div>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert cardiometabolic benefits beyond weight loss, yet their systemic proteomic mechanisms remain incompletely defined. We profiled short-term liraglutide-induced protein changes and compared them with published semaglutide signatures.</div></div><div><h3>Methods</h3><div>In a randomized, double-blind, placebo-controlled, crossover trial (<span><span>NCT02944500</span><svg><path></path></svg></span>), 20 adults with obesity received liraglutide 3 mg daily or placebo for 5 weeks, separated by a 3-week washout. Plasma and serum samples underwent SomaScan v4.1 profiling of 6249 proteins. Mixed-effects models tested Time×Treatment interactions with and without weight adjustment. Results were benchmarked against the 30-protein semaglutide STEP 1/2 signature.</div></div><div><h3>Results</h3><div>Liraglutide significantly modulated 124 proteins (57 FDR &lt; 0.05); 85 % of effects persisted after weight adjustment, indicating largely weight-independent actions. Upregulated proteins included pancreatic enzymes (PNLIP, CTRB1/2, PRSS2), while endothelial and fibrotic markers (ACE, NOS3, FAP) were downregulated. Myostatin (MSTN) was strongly suppressed (log₂ fold change −0.41; <em>p</em> = 1.7 × 10⁻⁶), with concurrent rises in its inhibitors WFIKKN2 and BMPR1A. Liraglutide shared 70–75 % directional overlap with semaglutide, with 25–30 % unique effects enriched in vascular, neurodevelopmental, and musculoskeletal pathways. A semaglutide-based classifier distinguished liraglutide from placebo (AUC = 0.82; sensitivity 0.89; specificity 0.60). Downregulated proteins were genetically linked to coronary artery disease and type 2 diabetes (FDR &lt; 0.05).</div></div><div><h3>Conclusions/interpretation</h3><div>Short-term liraglutide reproduces the core GLP-1RA proteomic fingerprint while uniquely suppressing myostatin and vascular remodeling pathways. These rapid, largely weight-independent molecular responses indicate early cardioprotective and myostatin-inhibitor signaling changes that could be relevant for future muscle-preserving strategies, supporting individualized GLP-1RA use beyond weight loss alone.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156493"},"PeriodicalIF":11.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945045","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}

{"title":"Essential role of endothelial T-cadherin in the transcytosis of circulating high-molecular-weight adiponectin to sub-vascular tissues","authors":"Shunsuke Shiode ,&nbsp;Yuya Fujishima ,&nbsp;Keita Fukuoka ,&nbsp;Saito Inoue ,&nbsp;Atsuya Shirono ,&nbsp;Keisuke Sirakura ,&nbsp;Yoshiaki Okada ,&nbsp;Yoshihisa Koyama ,&nbsp;Yuta Kondo ,&nbsp;Kohei Fujii ,&nbsp;Keitaro Kawada ,&nbsp;Hirofumi Nagao ,&nbsp;Yoshinari Obata ,&nbsp;Shiro Fukuda ,&nbsp;Shunbun Kita ,&nbsp;Shoichi Shimada ,&nbsp;Norikazu Maeda ,&nbsp;Hitoshi Nishizawa ,&nbsp;Iichiro Shimomura","doi":"10.1016/j.metabol.2025.156488","DOIUrl":"10.1016/j.metabol.2025.156488","url":null,"abstract":"<div><h3>Background</h3><div>Adiponectin, an adipocyte-derived protein, has diverse organ-protective effects, which are associated with its accumulation in vascular endothelial cells (VECs) as well as in various extravascular cell types, including skeletal muscle cells and cardiomyocytes. T-cadherin, a high-affinity binding partner for multimeric adiponectin, facilitates this accumulation; however, the mechanism by which high-molecular-weight (HMW) adiponectin transverses the endothelium remains unclear.</div></div><div><h3>Method and results</h3><div>We showed that tamoxifen-induced T-cadherin deficiency in VECs alone significantly increased plasma adiponectin levels, similar to inducible systemic T-cadherin deletion. The intravenous administration of adiponectin to adiponectin-deficient VEC-specific T-cadherin knockout mice markedly impaired the clearance of intravenously injected adiponectin, resulting in significant reductions in the accumulation of hexameric and HMW adiponectin, particularly the octadecameric (18-mer) form, not only in VECs, to note, but also in skeletal muscle and heart tissues. Furthermore, endothelial T-cadherin deficiency led to activation of innate immune signaling and cardiac remodeling, even under physiological conditions. In vitro experiments using MDCK II cells demonstrated that T-cadherin mediated the apical–to–basolateral transport of 18-mer adiponectin, largely preserving its HMW form. Additionally, intracellular adiponectin colocalized with the recycling endosome marker RAB11, and Rab11 deficiency significantly impaired its transcytosis. Similarly, in human VECs, T-cadherin knockdown significantly reduced basolateral adiponectin transport.</div></div><div><h3>Conclusions</h3><div>These findings identify vascular endothelial T-cadherin as a key mediator of HMW adiponectin transcytosis via the recycling endosome pathway, enabling its traversal from the circulation to sub-vascular tissues/cells and offering a mechanistic basis for the systemic organ-protective effects of adiponectin.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156488"},"PeriodicalIF":11.9,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903962","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}

{"title":"Incretin-based therapy and atrial fibrillation risk in overweight or obesity","authors":"Paschalis Karakasis ,&nbsp;Konstantinos Vlachos ,&nbsp;Nikolaos Fragakis ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2025.156491","DOIUrl":"10.1016/j.metabol.2025.156491","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156491"},"PeriodicalIF":11.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888879","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}

{"title":"Are GLP-1 receptor agonists associated with reduced atrial fibrillation risk? Analyzing data duplication and uncertainty","authors":"Lucas M. Barbosa ,&nbsp;Vinícius Martins Rodrigues Oliveira","doi":"10.1016/j.metabol.2025.156490","DOIUrl":"10.1016/j.metabol.2025.156490","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156490"},"PeriodicalIF":11.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888929","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}

{"title":"TRP channels at the crossroads of metabolism and immunity: ion–metabolite coupling in inflammation and disease","authors":"De-Hua Liao ,&nbsp;Shi-Long Jiang ,&nbsp;Ting Wu ,&nbsp;Zeng Cao ,&nbsp;Ze-Wu Zhu ,&nbsp;Nayiyuan Wu ,&nbsp;Xiu Zhang ,&nbsp;Ming-Hui Long ,&nbsp;Jing Wang ,&nbsp;Zhi-Bin Wang","doi":"10.1016/j.metabol.2025.156486","DOIUrl":"10.1016/j.metabol.2025.156486","url":null,"abstract":"<div><div>Transient receptor potential (TRP) channels are not only multimodal ion sensors but also couplers between metabolic states and immune responses. TRP gating is controlled by lipid signaling (PIP2, DAG, cholesterol), redox/energy cues (NAD⁺/ADPR/ROS, ATP/AMP), and metabolite-derived signals (pH/lactate, bile acids, endocannabinoids, eicosanoids, SCFAs). In turn, TRP-driven Ca²⁺ signaling reprograms AMPK–mTORC1, glycolysis/OXPHOS, FAO, and glutaminolysis, thereby reshaping the metabolic programs and effector functions of T/B cells, macrophages, NK/DCs. In gut, skin, and arthritis, microbiota–metabolite–TRP axes dictate inflammatory phenotypes; within tumors, lactate, adenosine, and kynurenine modulate TRPs in cancer and immune infiltrates. In this study, we synthesize TRP metabolic sensing mechanisms, immunometabolic reprogramming, and pharmacological opportunities, highlighting synergistic strategies combining metabolic interventions with TRP modulation for precision management of inflammation-related diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156486"},"PeriodicalIF":11.9,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878710","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}

{"title":"Suppression of hepatosteatosis by isarubrolone C through AMPK-dependent regulation of lipophagy and lipid metabolism","authors":"Bo Chen ,&nbsp;Yuan-yuan Ma ,&nbsp;Miao-qing Zhang ,&nbsp;Rui Zhang ,&nbsp;Shu-fen Li ,&nbsp;Lin-zhuan Wu ,&nbsp;Jing-pu Zhang","doi":"10.1016/j.metabol.2025.156487","DOIUrl":"10.1016/j.metabol.2025.156487","url":null,"abstract":"<div><div>Targeting autophagy and fatty acid metabolism may be two promising therapeutic strategies for treating metabolic dysfunction-associated steatotic liver disease (MASLD). Our previous research demonstrated the ability of isarubrolone C (IroC), a bioactive polycyclic tropoloalkaloid to induce autophagy. However, the effects and mechanisms of IroC on MASLD have yet to be explored. Here, we generated a steatosis cell model using a minimum essential medium containing oleic acid and palmitic acid (HFA) in HepG2 cells, and a zebrafish model of hepatic steatosis fed a high-fat diet (HFD), and explored the role and mechanism of IroC against hepatic steatosis. HFA and HFD exposure caused lipid accumulation, fatty acid oxidation (FAO) defect and high expression of lipogenesis genes, and IroC treatment reversed these steatosis-like features <em>in vitro</em> and in the liver of zebrafish with MASLD. Mechanistically, IroC increased AMPK phosphorylation that further phosphorylated ULK1, ACC, PPARα and full-length SREBP1, by which lipophagy and FAO damaged by HFA were recovered, expression of <em>de novo</em> lipogenesis genes reduced, including <em>fasn</em> and <em>scd1</em> expression <em>via</em> downregulation of SREBP-1 activity; and CD36 for FA transport was decreased by p-AMPK inhibition of PPARγ phosphorylation. Notably, IroC exhibited a high binding affinity to the AMPKα1β2γ1 isoform, as demonstrated by both molecular docking and surface plasmon resonance assay. Our work uncovers that IroC exerts an activator of AMPK, by which IroC can activate lipophagy and FAO, and inhibit lipogenesis and lipid deposition in hepatocytes. Thereby, IroC has the potential to serve as an effective agent in the management of MASLD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"176 ","pages":"Article 156487"},"PeriodicalIF":11.9,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145878702","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}