Metabolism: clinical and experimental最新文献

{"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":"2026-01-20","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":"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":"2026-01-20","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":"Multi-omics profiling reveals CKM syndrome severity as a gradient risk factor for cancer: A prospective cohort study","authors":"Yu Huang ,&nbsp;Yiwei Zhang ,&nbsp;Yanjun Zhang ,&nbsp;Ziliang Ye ,&nbsp;Sisi Yang ,&nbsp;Xiaoqin Gan ,&nbsp;Yiting Wu ,&nbsp;Yuanyuan Zhang ,&nbsp;Xianhui Qin","doi":"10.1016/j.metabol.2026.156508","DOIUrl":"10.1016/j.metabol.2026.156508","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 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 ,&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":"2026-01-13","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}