Metabolism: clinical and experimental最新文献

{"title":"Rising burden of MASLD and CKM syndrome in Asia: A decade of trends and future projections","authors":"Tianqi Duo , Yun Wen , Yu Bian , Yizheng Wang , Xiaofang Zhang , Jin Ju , Yanjie Lu , Zhiguo Wang , Jinghao Wang , Baofeng Yang","doi":"10.1016/j.metabol.2026.156549","DOIUrl":"10.1016/j.metabol.2026.156549","url":null,"abstract":"<div><h3>Objective</h3><div>To analyze epidemiological trends and project the future burden of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome in Asia using data from the Global Burden of Disease (GBD) Study. This analysis quantifies the substantial co-occurrence of MASLD and CKM syndrome, which together accounted for 50.9% of the total disease prevalence in Asia in 2021, by evaluating incidence, prevalence, deaths, and disability-adjusted life years (DALYs) from 2010 to 2021.</div></div><div><h3>Methods</h3><div>Data from the GBD 2021 database were used to assess the burden of MASLD and CKM syndrome in Asia. The study analyzed incidence, prevalence, deaths and DALYs for nine metabolic diseases or related conditions: MASLD, atrial fibrillation and flutter (AF/AFL), ischemic heart disease (IHD), hypertension heart disease (HHD), lower extremity peripheral arterial disease (PAD), type 2 diabetes mellitus (T2DM), stroke, and chronic kidney disease (CKD) due to hypertension (HTN) and T2DM. Age-standardized rates (ASRs) and estimated annual percentage changes (EAPCs) were calculated. The autoregressive integrated moving average (ARIMA) model was applied to forecast the trend of MASLD over the next 20 years. This model, widely used in time-series forecasting, identifies trends, cyclical variations, and random fluctuations to provide scientifically grounded projections.</div></div><div><h3>Results</h3><div>In 2021, the collective burden of the nine CKM-related conditions analyzed (including MASLD) accounted for 50.9% of total disease prevalence and 34.4% of all deaths in Asia, with 12.68 million deaths and 306.82 million DALYs. Among the nine metabolic diseases analyzed, MASLD had the highest incidence and prevalence, with MASLD-related liver cirrhosis (MASLD-LC) and MASLD-related steatohepatitis (MASLD-SH) affecting approximately 786.69 million and 786.65 million individuals, respectively. IHD and stroke were the leading causes of death and DALYs. Between 2010 and 2021, the incidence (MASLD-LC/MASLD-SH: +25.4%) and prevalence (MASLD-LC/MASLD-SH: +38.0%) of MASLD increased substantially. T2DM showed the greatest rise in age-standardized incidence rate (EAPC: +1.7%) and age-standardized prevalence rate (EAPC: +2.0%). Geographically, MASLD represented the predominant metabolic burden in most Asian countries, with the exception of Central and South Asia, where IHD prevailed. ARIMA projections suggest that the MASLD burden will continue to grow, with a projected increase in incidence of approximately 34% compared to 1990 levels (MASLD-LC: +34.01%; MASLD-SH: +34.04%), underscoring the need for timely and proactive interventions.</div></div><div><h3>Conclusion</h3><div>MASLD and CKM syndrome constitute a major and growing health challenge in Asia. These findings underscore the need for early diagnosis, targeted interventions, and comprehensive public health strategies. Future research should ","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"178 ","pages":"Article 156549"},"PeriodicalIF":11.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125631","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":"Efficacy and safety of sepiapterin versus sapropterin in patients with phenylketonuria: Results from the Phase 3, randomized, crossover, open-label, active-controlled AMPLIPHY trial","authors":"Maria Giżewska ,&nbsp;Anita Inwood ,&nbsp;Renáta Tyčová ,&nbsp;Suresh Vijay ,&nbsp;Olivia Fjellbirkeland ,&nbsp;Francjan van Spronsen ,&nbsp;Eva Maria Venegas-Moreno ,&nbsp;Laura Guilder ,&nbsp;Alberto Burlina ,&nbsp;Heidi Peters ,&nbsp;Murray Potter ,&nbsp;Urh Grošelj ,&nbsp;Anupam Chakrapani ,&nbsp;Amaya Bélanger-Quintana ,&nbsp;François Maillot ,&nbsp;Frank Rutsch ,&nbsp;Jean-Baptiste Arnoux ,&nbsp;Michel Tchan ,&nbsp;Kim Ingalls ,&nbsp;Zhenming Zhao ,&nbsp;Ania C. Muntau","doi":"10.1016/j.metabol.2026.156513","DOIUrl":"10.1016/j.metabol.2026.156513","url":null,"abstract":"<div><h3>Aim</h3><div>AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU).</div></div><div><h3>Methods</h3><div>AMPLIPHY was an international, Phase 3, two-part, open-label study in participants with PKU aged ≥2 years. Participants responsive to sepiapterin (60 mg/kg/day) in Part 1 (≥20% reduction in blood phenylalanine [Phe]) entered Part 2, a crossover treatment period, and were randomized 1:1 to alternative treatment sequences of sepiapterin (60 mg/kg/day, licensed dosage) and sapropterin (20 mg/kg/day, maximum licensed dosage) for 4 weeks each, with a 14-day washout between treatments. The primary endpoint was mean change in blood Phe from baseline to Weeks 3–4 of each treatment period (Part 2).</div></div><div><h3>Results</h3><div>Of 82 participants enrolled, 67 (81.7%) and 62 (75.6%) had reductions in blood Phe ≥20% and ≥30%, respectively, in Part 1. Sixty-two participants were randomized in Part 2 (mean [SD] age, 15.8 [10.8] years). In the primary analysis set (≥30% reduction in blood Phe in Part 1, <em>n</em> <em>=</em> 58), mean (SD) baseline blood Phe before sepiapterin and sapropterin treatment was 725.8 (302.1) and 790.4 (370.0) μmol/L, respectively. Least-squares mean (SE) reduction in blood Phe from baseline was −437.0 (28.0) and −256.6 (28.2) μmol/L, respectively, representing a least-squares mean difference of −180.4 μmol/L (95% CI: −229.5, −131.4; <em>p</em> &lt; 0.0001) and a relative 70% greater reduction with sepiapterin versus sapropterin. Both treatments were well tolerated, with safety profiles consistent with previous reports.</div></div><div><h3>Conclusions</h3><div>Sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe. No new safety signals were observed.</div><div>The trial was registered in the UK Clinical Study Registry, ISRCTN, on January 29, 2024 (ID number, ISRCTN79102999; <span><span>https://www.isrctn.com/ISRCTN79102999</span><svg><path></path></svg></span>).</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"178 ","pages":"Article 156513"},"PeriodicalIF":11.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093576","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":"Serum Response Factor (SRF) promotes actin cytoskeletal organization in adipocytes to support adaptive hypertrophic expansion and tissue remodeling during obesity in mice","authors":"Jisun So ,&nbsp;Jamie Wann ,&nbsp;Kyungchan Kim ,&nbsp;Solaema Taleb ,&nbsp;Hyeong-Geug Kim ,&nbsp;Manju Kumari ,&nbsp;Alexander S. Banks ,&nbsp;X. Charlie Dong ,&nbsp;Hyun Cheol Roh","doi":"10.1016/j.metabol.2026.156548","DOIUrl":"10.1016/j.metabol.2026.156548","url":null,"abstract":"<div><h3>Background</h3><div>Adipocyte hypertrophy, the unique capacity of adipocytes to enlarge in response to energy surplus, is a crucial determinant of metabolic health during obesity. Nonetheless, the molecular mechanisms governing this adaptive growth remain incompletely characterized.</div></div><div><h3>Methods</h3><div>Super-enhancer landscapes in adipocytes were mapped <em>via</em> H3K27ac chromatin immunoprecipitation sequencing analysis of adipocyte nuclei from mice fed either a standard chow diet or high-fat diet (HFD) to identify transcriptional regulators activated under obesogenic conditions. Functional validation was conducted through both <em>in vitro</em> and <em>in vivo</em> experiments, including adipocyte-specific gene deletion mouse models, followed by single-nucleus RNA sequencing.</div></div><div><h3>Results</h3><div>Super-enhancer profiling identified Serum Response Factor (SRF) as a critical driver of actin cytoskeletal remodeling in adipocytes during obesity. SRF was shown to be both necessary and sufficient for regulation of actin cytoskeletal gene expression in 3T3-L1 adipocytes. Adipocyte-specific SRF ablation in mice led to reduced expression of actin cytoskeletal genes, disruption of actin filament organization, and impaired adipocyte enlargement under HFD feeding. Despite comparable body weight, SRF-deficient mice developed exacerbated insulin resistance and ectopic lipid accumulation in the liver and brown adipose tissue, indicative of compromised lipid storage within adipocytes. Single-nucleus RNA-seq further revealed that cell-intrinsic actin cytoskeletal defects in adipocytes propagated to tissue-level dysfunction, impairing vascularization and increasing inflammation.</div></div><div><h3>Conclusion</h3><div>These findings establish SRF as a central regulator of actin cytoskeletal organization that promotes healthy adipocyte hypertrophy and adipose tissue remodeling. Enhancing SRF-dependent cytoskeletal remodeling in adipocytes may offer a therapeutic strategy to preserve metabolic health in obesity.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"178 ","pages":"Article 156548"},"PeriodicalIF":11.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146142974","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":"The multifaceted role of GLP-1 in metabolic disorders, chronic inflammation, and aging: Mechanisms and therapeutic potential","authors":"Mo Li ,&nbsp;Shenghao Xu ,&nbsp;Hanqing Cai ,&nbsp;Jianlin Xiao ,&nbsp;Yanguo Qin","doi":"10.1016/j.metabol.2026.156547","DOIUrl":"10.1016/j.metabol.2026.156547","url":null,"abstract":"<div><div>Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells in response to nutrients, regulates glucose homeostasis by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite via hypothalamic signaling. Beyond these canonical actions, emerging evidence reveals GLP-1's pleiotropic functions across multiple systems, with relevance to metabolic disorders, chronic inflammation, and aging-related pathologies. This review summarizes molecular mechanisms underlying GLP-1's protective roles, highlighting its contributions to metabolic balance, inhibition of NF-κB-mediated inflammation, and attenuation of cellular aging through mitochondrial enhancement and autophagy promotion. GLP-1 also influences immune cell function and alleviates hallmarks of senescence, thereby offering therapeutic potential beyond diabetes. We further critically assess the translational potential of GLP-1 receptor agonists (GLP-1RAs), pharmacological agents with superior pharmacokinetics versus native GLP-1, in treating conditions linked to dysregulated metabolism, persistent inflammation, and accelerated aging. Despite demonstrated efficacy in preclinical models and clinical studies, important challenges persist, including inter-individual variability, off-target risks, and uncertainties regarding long-term safety. We conclude by emphasizing the necessity of integrated strategies to target the metabolic–inflammatory–aging axis and by advocating optimization of GLP-1RA formulations, identification of predictive biomarkers, and expansion of their utility for age-associated diseases.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"178 ","pages":"Article 156547"},"PeriodicalIF":11.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165695","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":"Emerging incretin- and multi-agonist-based treatments – the continued refinement and continuous expansion of a potent therapeutic armamentarium for cardio-kidney-liver-metabolic diseases and beyond","authors":"Emir Muzurović ,&nbsp;Niki Katsiki ,&nbsp;Špela Volčanšek ,&nbsp;Fulvio Plescia ,&nbsp;Manfredi Rizzo ,&nbsp;Christos S. Mantzoros","doi":"10.1016/j.metabol.2026.156494","DOIUrl":"10.1016/j.metabol.2026.156494","url":null,"abstract":"<div><div>While the use of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) has achieved a central position in our therapeutic armamentarium, new and innovative incretin- and multi-agonist-based treatment strategies hold further promise as potential game-changers for obesity and cardio-kidney-liver-metabolic diseases. Molecular pathways of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), amylin, glucagon and peptide YY have been consistently involved in improved outcomes associated with obesity and related disorders. Single, dual, and even triple drug combinations are being researched throughout all phases of clinical trials. The similarities in GLP-1, GIP, and glucagon peptide sequences enable the development of unimolecular multi-receptor activating agonists and/or antagonists. Furthermore, subcutaneously administered peptides are being supplemented with oral analogs currently in development. Both well-designed clinical trials and real-world evidence are fuelling the development of incretin and multi-agonist-based therapies, thereby holding the promise to deliver an increasing double-digit percent weight loss in addition to addressing many obesity-related comorbidities and complications. It is increasingly evident that early initiation of incretin-based therapy across a broad spectrum of cardio-kidney-metabolic disorders improves body weight, dysglycemia, and cardiovascular risk factor management and consequently is expected to reduce cardio-kidney-liver-metabolic and vascular morbidity and mortality and soon most probably those from obesity-related malignancies, Alzheimer's, and other neurocognitive diseases. This review explores new incretin- and multi-agonist-based therapies undergoing clinical trials for chronic weight management, type 2 diabetes mellitus with its complications, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease and obstructive sleep apnea; it also highlights areas of uncertainty regarding the potency, safety, tolerability, and sustainability of incretin-based approaches for obesity and cardio-kidney-liver-metabolic disorders and finally, we discuss future directions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156494"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018908","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 ,&nbsp;Sara Russo ,&nbsp;Marcello Pompa ,&nbsp;Andrea De Gaetano ,&nbsp;Ornella Verrastro ,&nbsp;Dario Tuccinardi ,&nbsp;Caterina Guidone ,&nbsp;Lidia Castagneto Gissey ,&nbsp;Giovanni Casella ,&nbsp;James R. Casella Mariolo ,&nbsp;Giulia Angelini ,&nbsp;Francois Pattou ,&nbsp;Silvia Sabatini ,&nbsp;Amalia Gastaldelli ,&nbsp;Paul W. Franks ,&nbsp;Ebaa Al Ozairi ,&nbsp;Thomas Sparso ,&nbsp;Stefan Bornstein ,&nbsp;Carel W. Le Roux ,&nbsp;Geltrude Mingrone","doi":"10.1016/j.metabol.2026.156495","DOIUrl":"10.1016/j.metabol.2026.156495","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Findings</h3><div>RYGB showed significantly greater weight loss than SG at both 12 (30.3% vs. 25.4%; <em>p</em> &lt; 0.001) and 24 months (26.3% vs. 21.4%; p &lt; 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.</div></div><div><h3>Interpretation</h3><div>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.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156495"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","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":"2026-04-01","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":"Integrative functional genomics and fine-mapping identify regulatory mechanisms of multivariate obesity GWAS and its cardiometabolic implications","authors":"Suijian Wang ,&nbsp;Sihua Liu ,&nbsp;Hongqiang Zhang ,&nbsp;Lijie Sun ,&nbsp;Huiling Tan ,&nbsp;Yu Shi ,&nbsp;Lanxin Pan ,&nbsp;Mengya Geng ,&nbsp;Minghui Chen ,&nbsp;Beibei Gao ,&nbsp;Kui Wang ,&nbsp;Haoqiang Zhang ,&nbsp;Tong Yue ,&nbsp;Jianping Weng ,&nbsp;Xueying Zheng","doi":"10.1016/j.metabol.2026.156509","DOIUrl":"10.1016/j.metabol.2026.156509","url":null,"abstract":"<div><h3>Background</h3><div>Obesity is a systemic disorder with heterogeneous fat distribution and complex metabolic complications. Conventional genome-wide association studies (GWAS) typically analyze individual obesity-related traits separately, limiting the identification of shared genetic architecture and key regulatory mechanisms, particularly those involving non-coding variants.</div></div><div><h3>Methods</h3><div>We integrated GWAS data for five obesity traits (body mass index, waist circumference, visceral fat, liver fat, and body fat percentage) using genomic structural equation modeling (GSEM) to construct a multivariate phenotype (mvObesity). Functional genomic integration combined adipose chromatin accessibility, enhancer promoter interactions, and expression quantitative trait loci (eQTL) data with transcriptome-wide and proteome-wide (TWAS and PWAS) analyses, fine-mapping, and colocalization. Trait-relevant cell types were identified using single-cell and single-cell polygenic association of GWAS (scPagwas) analyses.</div></div><div><h3>Results</h3><div>Multi-omics integration in adipose tissue identified 799 independent SNPs across 548 loci, including 45 previously unreported signals. Fine-mapping and TWAS defined 150 high-confidence candidate genes enriched for neuronal signaling, synaptic organization, and lipid metabolism pathways. MAGMA-based enrichment further revealed significant overrepresentation in brain regions such as the cerebellum, hippocampus, and hypothalamus, indicating central regulatory involvement. Single-cell analyses highlighted adipocytes, preadipocytes, and smooth muscle cells as major genetically influenced types, while cross-tissue TWAS and scRNA-seq supported coordinated neuro-metabolic transcriptional regulation. Multi-omic prioritization identified key genes such as <em>MED13L</em>, <em>GBE1</em>, <em>CADM2</em>, <em>PIK3R3</em>, <em>ERBB4</em>, and <em>PTK2B</em> and demonstrated significant genome-wide and local genetic overlap between mvObesity and cardiometabolic traits.</div></div><div><h3>Conclusions</h3><div>This multivariate, multi-omics framework delineates a cross-tissue neuro-adipose regulatory axis underlying obesity, providing mechanistic insight and a genetically informed candidate framework for future precision metabolic intervention research.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156509"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030203","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":"2026-04-01","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":"Natural polyketide enterocin inhibits ASGR1 to enhance cholesterol efflux and regulate hepatic lipid metabolism","authors":"Yan Liu ,&nbsp;Jiahao Pang ,&nbsp;Manru Ma ,&nbsp;Pengfei Xu ,&nbsp;Zhifeng Tang ,&nbsp;Yu Guo ,&nbsp;Rui Liu ,&nbsp;Xiaoping Peng ,&nbsp;Hongxiang Lou ,&nbsp;KeWei Wang ,&nbsp;Gang Li ,&nbsp;Limei Wang","doi":"10.1016/j.metabol.2026.156511","DOIUrl":"10.1016/j.metabol.2026.156511","url":null,"abstract":"<div><div>The discovery of novel, targeted cholesterol-lowering agents holds clinical value for cardiovascular disease (CVD) prevention and management. Here, we report the isolation of a naturally occurring polyketide, enterocin, from the marine-derived <em>Streptomyces</em> sp. FXY-T25 using a cholesterol-modulating activity-guided assay. Enterocin, with a unique tricyclic caged core skeleton, enhanced cholesterol efflux in Huh-7 and HepG2 liver cells by directly binding to ASGR1 and promoting its proteasomal degradation without transcriptional alteration. This ASGR1 inhibition triggered AMPKα activation and subsequent LXRα-mediated upregulation of cholesterol efflux. The accelerated degradation of ASGR1 was confirmed to be proteasome-dependent, as evidenced by lysosomal or proteasomal inhibitors. In high-fat-diet (HFD)-fed wild-type mice, enterocin significantly reduced visceral and subcutaneous fat, improved serum lipid profiles (decreasing TC, TG, and LDL-C while elevating HDL-C), attenuated hepatic lipid accumulation, and enhanced fecal cholesterol excretion. Consistent with the in vitro findings, enterocin downregulated hepatic ASGR1 protein levels and subsequently activated the AMPKα-LXRα-ABCA1/G1/G5/G8 pathway in mouse liver. In HFD-fed LDLR^−/− mice, enterocin exhibited lipid-lowering activity comparable or superior to that of the positive controls atorvastatin and GW3965. Notably, enterocin demonstrated no significant effect on intestinal fat absorption, highlighting its targeted activity in hepatic cholesterol metabolism. These findings establish enterocin as a novel therapeutic candidate that uniquely modulates cholesterol homeostasis, offering potential for the treatment of both hypercholesterolemia and metabolic dysfunction-associated fatty liver disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156511"},"PeriodicalIF":11.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044244","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}