Metabolism: clinical and experimental最新文献

{"title":"Corrigendum to “Eva1 deficiency prevents obesity-induced metabolic disorders by reducing visceral adipose dysfunction” [Metabolism 168 (2025) 156235]","authors":"You Lee Son , Jiahui Hou , Mira Kato-Suzuki , Yuko Okamatsu-Ogura , Megumi Watase , Hiroshi Kiyonari , Toru Kondo","doi":"10.1016/j.metabol.2025.156299","DOIUrl":"10.1016/j.metabol.2025.156299","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156299"},"PeriodicalIF":10.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147752","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":"On the misinterpretation of metabolites as causal mediators between meat intake and cardiovascular risk.","authors":"Yang Zhang, Fanwu Chi, Ren Zhu, Lian Hu","doi":"10.1016/j.metabol.2025.156305","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156305","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156305"},"PeriodicalIF":10.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181205","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 chemokine CCL20 promotes hepatocyte cholesterol deposition during metabolic dysfunction-associated steatohepatitis by regulating OLR1 expression.","authors":"Min Yin, Yan Zhang, Suosi Liu, Qianrong Wang, Yu Zhang, Jiali Min, Jiahui Yang, Yuyan Zhao, Zhiguang Zhou, Xia Li, Shanshan Liu","doi":"10.1016/j.metabol.2025.156301","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156301","url":null,"abstract":"<p><strong>Background & aims: </strong>Metabolic dysfunction-associated steatohepatitis (MASH) is becoming a leading driver of liver failure and transplantation. The specific pathogenic mechanisms driving MASH remain incompletely understood. In this study, we aimed to investigate the role of CCL20 in MASH progression.</p><p><strong>Methods: </strong>Using RNA sequencing data and murine models of MASH, we analyzed the expression levels of CCL20 in liver tissues, as well as the correlation of CCL20 levels with liver function parameters. Hepatic CCL20-knockdown and hepatic progenitor cell (HPC)/cholangiocyte-specific CCL20-knockout mice were used to assess the role of CCL20 in hepatic steatosis and inflammation. The mechanisms by which CCL20 influences MASH were explored via in vitro and in vivo gain- and loss-of-function approaches.</p><p><strong>Results: </strong>We observed that CCL20 is significantly upregulated in MASH livers from mice and humans and that hepatic CCL20 expression is positively correlated with MASH severity. CCL20, which is mainly produced by HPCs/cholangiocytes, is transcriptionally activated by RELB and SOX9. In mice, CCL20 knockout in HPCs/cholangiocytes attenuated pathological changes in the liver. Mechanistically, by binding to CCR6, CCL20 activates the JNK signaling pathway, which increases OLR1 expression, thereby promoting oxLDL uptake and cholesterol deposition in hepatocytes.</p><p><strong>Conclusion: </strong>These findings implicate the CCL20-CCR6-JNK-OLR1 axis as a crucial determinant of MASH progression and highlight CCL20 inhibition as an attractive therapeutic strategy for MASH.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156301"},"PeriodicalIF":10.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174254","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":"Targeting SAMD1 enhances the effect of anti-PD-1 plus lenvatinib therapy in hepatocellular carcinoma by increasing ferroptosis sensitivity and immune response.","authors":"Guo-Qiang Pan, Yu-Chuan Yan, Rui-Zhe Li, Chen Xiong, Shao-Peng Zhang, Ying Qu, Rui Dong, Yu Zhou, Tuan-Song Zhang, Zhi-Qiang Chen, Xiao-Lu Zhang, Xiao-Feng Dong, Dong-Xu Wang, Zhao-Ru Dong, Tao Li","doi":"10.1016/j.metabol.2025.156304","DOIUrl":"https://doi.org/10.1016/j.metabol.2025.156304","url":null,"abstract":"<p><strong>Background: </strong>Combination therapy of anti-PD-1 plus lenvatinib has shown effective anti-tumour effects for unresectable hepatocellular carcinoma (HCC), but the overall prognosis of HCC is still unsatisfactory. Elucidating the molecular mechanism underlying HCC progression contributes to develop new effective treatment in order to enhances the response of anti-PD-1 plus lenvatinib therapy and improve the patients prognosis.</p><p><strong>Method and results: </strong>Here, we reported that targeting SAMD1 in HCC cells via small interference RNA-containing ZIF-90@HA (ATP/acid-responsive) Nanoparticles (ZIF-90@siRNA@HA NPs, ZSH NPs) significantly enhanced the anti-tumour effects of anti-PD-1 plus lenvatinib in vivo. Targeting SAMD1 in HCC cells not only increased cellular ROS abundance by inhibiting glycolysis and enhancing oxidative phosphorylation (OXPHOS) to increase ferroptosis sensitivity, but also inhibited the expression of CCL28, thereby reducing the recruitment of Treg cells, and improving the immunosuppression of tumour microenvironment. Mechanistically, SAMD1 suppression inhibits the expression of NUAK2 via Hippo pathway, thereby decreasing the phosphorylation of PFKP Ser386 and promoting the ubiquitination degradation of PFKP in HCC. Further study demonstrated that SAMD1 inhibition increased the expression of ITIH5 by regulating H3K4me3 demethylation at the ITIH5 promoter and then regulates Hippo pathway.</p><p><strong>Conclusions: </strong>Our study revealed the potential application of targeting SAMD1 in HCC treatment by enhancing ferroptosis sensitivity and immune response.</p>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":" ","pages":"156304"},"PeriodicalIF":10.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143000","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":"Impact of metabolic dysfunction severity in steatotic liver disease and its interaction with liver fibrosis on all-cause mortality and multiple hepatic and extra-hepatic outcomes","authors":"Daniel J. Cuthbertson ,&nbsp;Oliver J. Kennedy ,&nbsp;Josh Bilson ,&nbsp;Theresa J. Hydes ,&nbsp;Giovanni Targher ,&nbsp;Kate Glyn-Owen ,&nbsp;Ryan Buchanan ,&nbsp;Paul Roderick ,&nbsp;Christopher D. Byrne","doi":"10.1016/j.metabol.2025.156306","DOIUrl":"10.1016/j.metabol.2025.156306","url":null,"abstract":"<div><h3>Background</h3><div>In metabolic dysfunction-associated steatotic liver disease (MASLD) and in MASLD with alcohol consumption (MetALD), we investigated the effect of severity of metabolic dysfunction on incident major adverse liver outcomes (MALO), major cardiovascular events (MACE), obesity-related cancers, and all-cause mortality (ACM).</div></div><div><h3>Methods</h3><div>SLD was identified among 502,381 UK Biobank participants using the Hepatic Steatosis Index (HSI) (&gt;36 <em>vs.</em>&lt;30). Metabolic syndrome (MetS) traits and MetS (≥3 traits) using MASLD/MetALD criteria. Cox regression was used to estimate adjusted hazard ratios and 95%CIs [aHR(95%CIs)] of MASLD or MetALD <em>plus</em> 1 to 5 MetS traits with incident MALO, MACE, obesity-related cancers and 5-year/10-year incidence rates <em>versus</em> reference (no SLD/MetS traits).</div></div><div><h3>Results</h3><div>Median follow-up was 148 to 149 months. Comparing MASLD with one <em>versus</em> five MetS traits, respectively, to the reference; for MALO, [aHRs (95%CIs)] were 2.27 (1.03–5.00) and 9.19 (4.98–16.95); for MetALD, aHRs were 1.65 (0.53–5.11) and 8.54 (3.65–19.95) respectively. For MACE, with MASLD; aHRs were 1.51 (1.19–1.92) and 4.81 (4.06–5.69) respectively; with MetALD, aHRs were 1.46 (1.00–2.13) and 4.64 (3.51–6.14) respectively. For obesity-related cancers; with MASLD, aHRs were 1.04 (0.87–1.23) and 1.46 (1.29–1.66) respectively; with MetALD, aHRs were 1.01 (0.79–1.29) and 1.51 (1.24–1.83) respectively. 5-year and 10-year incidence rates also increased progressively with increasing MetS traits. Combining SLD, MetS and high liver fibrosis risk (defined by FIB-4 ≥ 2.67) was strongly associated with MALO in both MASLD and MetALD (aHRs 27.48, (17.72–42.61); 43.36, 20.53–91.58 respectively).</div></div><div><h3>Conclusion</h3><div>In MASLD or MetALD, the numbers of MetS traits markedly influence risk and incidence of liver-related outcomes, MACE, obesity-related cancers and ACM.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156306"},"PeriodicalIF":10.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142935","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":"Exploring the interplay of genetic variants and environmental factors in childhood obesity: A systematic review and meta-analysis","authors":"Haoxue Zhu ,&nbsp;Xinghao Yi ,&nbsp;Mengyu He ,&nbsp;Siyi Wu ,&nbsp;Ming Li ,&nbsp;Shan Gao","doi":"10.1016/j.metabol.2025.156303","DOIUrl":"10.1016/j.metabol.2025.156303","url":null,"abstract":"<div><div>Dynamic interactions between genetic predispositions and environmental exposures significantly shape the escalating prevalence of childhood obesity. This systematic review synthesizes observational and clinical trial evidence on the gene-environment interplays influencing childhood obesity, highlighting the role of genetic variants and environmental moderators such as dietary habits, physical activity, sleep durations, parental behaviors, socioeconomic status, ethnicity, gender, as well as lifestyle interventions. We conducted an exhaustive search across 5 databases (Medline, PubMed, EMBASE, Web of Science, and Cochrane Library), adhering to PRISMA guidelines. We ultimately included 147 studies that investigated these interplays in diverse populations. Specifically, 83 studies focused on gene-diet interplays, 23 on gene-physical activity, 5 on sedentary behavior, 3 on screen time, 7 on sleep duration, 10 on parental behavior, 4 on socioeconomic status, 16 on gender, 8 on age, 7 on ethnicity, and 13 on the effects of lifestyle interventions. Notably, we meta-analyzed energy expenditure and macronutrient consumption, including carbohydrates, proteins, and fats, as well as the proportion of energy supplied by each nutrient between carriers and noncarriers of the FTO effect allele, revealing that carriers consumed a higher proportion of fat calories, with no other significant differences noted. This review demonstrates that genetic risk variants, particularly in FTO (e.g., rs9939609) and MC4R (e.g., rs17782313), amplify the adverse effects of obesogenic behaviors, offering insights into the intricate pathophysiology of childhood obesity and suggesting the potential for personalized interventions based on genetic profiles.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156303"},"PeriodicalIF":10.8,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138091","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":"Overview of methods that determine mitochondrial function in human disease","authors":"Eashan Sharma ,&nbsp;Leila Fotooh Abadi ,&nbsp;John Arnaud Kombe Kombe ,&nbsp;Monisha Kandala ,&nbsp;Jordan Parker ,&nbsp;Nolan Winicki ,&nbsp;Theodoros Kelesidis","doi":"10.1016/j.metabol.2025.156300","DOIUrl":"10.1016/j.metabol.2025.156300","url":null,"abstract":"<div><div>Cellular metabolism has a key role in the pathogenesis of human disease. Mitochondria are the organelles that generate most of the energy needed for a cell to function and drive cellular metabolism. Understanding the link between metabolic and mitochondrial function can be challenging due to the variation in methods used to measure mitochondrial function and heterogeneity in mitochondria, cells, tissues, and end organs. Mitochondrial dysfunction can be determined at both the cellular and tissue levels using several methods, such as assessment of cellular bioenergetics, levels of mitochondrial DNA (mtDNA), mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mito-ROS), and levels of mitochondrial enzymes. Recent advances involving novel radiotracers in combination with PET imaging have allowed for the determination of mitochondrial function in vivo with high specificity. Understanding the barriers in existing methodologies used to study mitochondrial function may help further establish the assessment of mitochondrial function as a biologically and clinically relevant biomarker for human disease severity and prognosis. Herein, we critically review the existing literature regarding the strengths and limitations of methods that determine mitochondrial function, and we subsequently discuss how emerging research methods have begun to overcome some of these hurdles. We conclude that a combination of techniques, including respirometry and mitochondrial membrane potential assessment, is necessary to understand the complexity and biological and clinical relevance of mitochondrial function in human disease.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156300"},"PeriodicalIF":10.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102016","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":"Chemical discovery of a novel MD2/ADAM17 dual-target inhibitor as a potential therapeutic candidate for saturated fatty acid-induced myocardial inflammatory injury","authors":"Xiao-dan Zhang ,&nbsp;Yun-shan Zhong ,&nbsp;Hao Yan ,&nbsp;Le-hao Jin ,&nbsp;Jing Chen ,&nbsp;Zhong-xi Chen ,&nbsp;Zhe-yan Zhang ,&nbsp;Yun-jie Zhao ,&nbsp;Jian-chang Qian","doi":"10.1016/j.metabol.2025.156298","DOIUrl":"10.1016/j.metabol.2025.156298","url":null,"abstract":"<div><h3>Background and aims</h3><div>While the therapeutic promise of anti-inflammatory interventions for obesity-associated cardiomyopathy is well recognized, clinically effective targeted therapies remain to be developed. Here, through systematic anti-inflammatory screening, we elucidated both the therapeutic efficacy and mechanistic basis of a novel indole-substituted acetamide derivative (compound #3) in mitigating obesity-induced cardiomyopathy.</div></div><div><h3>Methods</h3><div>A high-fat diet (HFD)-induced obese mouse model was used to evaluate the cardioprotective efficacy of compound #3. Integrated <em>in vivo</em> and <em>in vitro</em> studies, including transcriptomics, reverse molecular docking, proteomics, surface plasmon resonance, and kinase activity assays, were conducted to systematically identify molecular targets and elucidate the underlying mechanisms.</div></div><div><h3>Results</h3><div>Compound #3 attenuated hypertension in HFD-induced obese mice without altering metabolic parameters (body weight, blood glucose, and lipid levels). This cardioprotective effect was attributed to improved cardiac function and anti-inflammatory mechanisms, including the suppression of NF-κB-driven inflammatory injury. Mechanistic studies revealed that compound #3 targeted the L348 residue of ADAM17, disrupting ADAM17-dependent inflammatory signal amplification. This cascade was primarily initiated by the MD2-P38MAPK/JNK-iRhom2 axis. In addition, compound #3 directly bound to MD2, inhibiting palmitic acid (PA)-induced activation of P38MAPK and JNK. This mechanism blocked the initiation of inflammatory responses and further suppressed ADAM17 and cytokine transcription through the P38MAPK-AP1 axis.</div></div><div><h3>Conclusion</h3><div>Compound #3 exhibits a dual-targeting mechanism by simultaneously inhibiting MD2 and ADAM17, which effectively suppresses both the initiation (via the MD2-P38MAPK/JNK) and amplification (via the P38MAPK/JNK-iRhom2-ADAM17 axis) of inflammatory cascades, highlighting its strong therapeutic promise for treating saturated fatty acid-induced myocardial pathologies.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156298"},"PeriodicalIF":10.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094362","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":"Use of finerenone in patients with chronic kidney disease at high risk of heart failure","authors":"John P. Hakim ,&nbsp;Yehuda Handelsman ,&nbsp;Trina Banerjee","doi":"10.1016/j.metabol.2025.156297","DOIUrl":"10.1016/j.metabol.2025.156297","url":null,"abstract":"<div><div>Treatment of symptomatic/advanced heart failure (HF) in patients who also have chronic kidney disease (CKD) and type 2 diabetes (T2D) may include a steroidal mineralocorticoid receptor antagonist (MRA). However, patients with CKD and T2D who are at high risk of developing HF may benefit from taking the nonsteroidal MRA finerenone. Results from phase 3 placebo-controlled trials of finerenone in patients with CKD associated with T2D showed that finerenone (plus a renin-angiotensin-aldosterone system inhibitor) reduced the risk of new-onset HF, improved other HF outcomes, and caused a significant slowing of CKD progression. Those who work in cardiology need to be aware of the HF risk-reduction effects of finerenone in patients with CKD and T2D. In this review, we provide a rationale for finerenone use in cardiology based on the available finerenone clinical trial data and from the perspective of a cardiologist who prescribes finerenone to patients who have comorbid CKD and T2D.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"169 ","pages":"Article 156297"},"PeriodicalIF":10.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069996","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":"Evaluation of tetrahydropyridazine-based peripherally restricted dual inhibitors of CB1R and inducible nitric oxide synthase (iNOS) for treating metabolic syndrome disorders","authors":"Pinaki Bhattacharjee ,&nbsp;Szabolcs Dvorácskó ,&nbsp;Océane Pointeau ,&nbsp;Biswajit Kundu ,&nbsp;Nicholas Rutland ,&nbsp;Henry Puhl III ,&nbsp;Jie Liu ,&nbsp;Grzegorz Godlewski ,&nbsp;Sergio A. Hassan ,&nbsp;Tony Jourdan ,&nbsp;Resat Cinar ,&nbsp;Malliga R. Iyer","doi":"10.1016/j.metabol.2025.156291","DOIUrl":"10.1016/j.metabol.2025.156291","url":null,"abstract":"<div><h3>Background and purpose</h3><div>The endocannabinoid system is a key regulator of metabolism, sparking interest in cannabinoid type 1 receptor (CB1R) antagonists as potential treatments for obesity and related conditions collectively called metabolic syndrome disorders. However, the neuropsychiatric liabilities associated with centrally acting CB1R antagonists led researchers to focus on developing peripherally restricted compounds that do not cross the blood-brain barrier (BBB).</div><div>This study aimed to synthesize and evaluate novel CB1R antagonists based on tetrahydropyridazine core incorporating physicochemical design principles that would allow for negligible BBB penetration. The efficacy of the compounds was assessed in rodent models of diet induced obesity and diabetes.</div></div><div><h3>Experimental approach</h3><div>In this study, we employed a rational-design approach along with structure-based modeling to develop small-molecule CB1R antagonists that are peripherally acting. Pharmacological profiles of two racemic compounds PB19A and PB95 were evaluated in cannabinoid receptor binding studies, and functional [³⁵S]-GTPγS assays. Further chiral separation of enantiomers allowed for the evaluation of respective eutomers in in vitro ADME studies along with in vivo pharmacokinetic and tissue distribution studies in mice. The results showed that the compounds are orally bioavailable and had negligible brain penetrance. The design features also incorporated putative amidine moieties which inhibit the pro-inflammatory enzyme; inducible nitric oxide synthase (iNOS). Both biochemical and in vitro cell-based assays showed the CB1R antagonists having iNOS inhibitor properties. In vivo CB1R functional antagonism was assessed by upper gastrointestinal motility assay. The efficacy of our CB1R antagonists was compared with brain penetrant ibipinabant in a diet-induced obesity mouse model, assessing effects on lipid metabolism biomarkers, food intake, body weight reduction, glucose tolerance and insulin resistance.</div></div><div><h3>Key results</h3><div>Novel compounds PB19AE2 and PB95E2 were designed and evaluated as peripherally restricted CB1R antagonists. In high fat diet fed mice, these compounds improved metabolic parameters, modestly reduced food intake, and ameliorated hepatic lipid metabolism markers.</div></div><div><h3>Conclusion and implications</h3><div>Overall, PB19AE2 and PB95E2 are orally bioavailable, peripherally acting CB1 antagonists and their preliminary evaluation show promising potential in utilizing the pyridazine-based compounds for generating potent leads for treating obesity- associated disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"170 ","pages":"Article 156291"},"PeriodicalIF":10.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144079111","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}