Metabolism: clinical and experimental最新文献

{"title":"From liver to vasculature: An integrated view of cardiovascular risk in hepatic steatosis.","authors":"Xun Hu, Long Long","doi":"10.1016/j.metabol.2026.156550","DOIUrl":"10.1016/j.metabol.2026.156550","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156550"},"PeriodicalIF":11.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100420","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":"Reply: From liver to vasculature: An integrated view of cardiovascular risk in hepatic steatosis.","authors":"Shady Abohashem, Midori N Torpoco Rivera, Michael T Osborne","doi":"10.1016/j.metabol.2026.156551","DOIUrl":"10.1016/j.metabol.2026.156551","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156551"},"PeriodicalIF":11.9,"publicationDate":"2026-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100492","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":"2026-01-28","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":"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":"2026-01-22","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}

{"title":"HMGCS2 desuccinylation modulates acetoacetate to drive tubule-macrophage inflammatory crosstalk in diabetic kidney disease","authors":"Ziyue Lin ,&nbsp;Dan Lv ,&nbsp;He Zha ,&nbsp;Handeng Liu ,&nbsp;Rui Peng ,&nbsp;Jiakun Yang ,&nbsp;Wuchao Li ,&nbsp;Xiaohui Liao ,&nbsp;Yan Sun ,&nbsp;Zheng Zhang","doi":"10.1016/j.metabol.2026.156510","DOIUrl":"10.1016/j.metabol.2026.156510","url":null,"abstract":"<div><div>Mitochondrial dysfunction in renal tubular epithelial cells (TECs) is a hallmark of diabetic kidney disease (DKD), accompanied by macrophage infiltration, yet how metabolic perturbations in TECs-macrophage driven inflammation remains unclear. Here, we identify 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the rate-limiting enzyme of ketogenesis, as a critical mediator linking tubular mitochondrial stress to macrophage M1 polarization in DKD. In mice subjected to DKD, conditional knockout HMGCS2 in TECs decreases mitochondrial fission of TECs, M1 macrophage infiltration and tubular inflammatory injury. Combining LC-MS/MS and ketone flux detection reveals that desuccinylated HMGCS2 produced more acetoacetate (AcAc) than beta-hydroxybutyrate (β-HB) in TECs of DKD. Mechanistically, Signal Transducer and Activator of Transcription 3 (STAT3) promotes <em>Hmgcs2</em> transcription and sirtuin 5 (SIRT5) activates HMGCS2 through lysine desuccinylation at K367, which promotes AcAc overload shuttling from TECs to macrophages. AcAc acts as a signaling metabolite to activate the MIF/ERK pathway, driving M1 polarization and amplifying a pro-inflammatory feedback loop of tubular injury. In addition, AAV9-mediated <em>Hmgcs2</em> silencing therapy improves tubular inflammatory injury and attenuates DKD progression. Taken together, this study unveils a tubule-macrophage metabolic crosstalk axis mediated by HMGCS2-driven AcAc accumulation, which couples mitochondrial stress to immune response in DKD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"177 ","pages":"Article 156510"},"PeriodicalIF":11.9,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035399","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":"2026-01-20","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}