Metabolism: clinical and experimental最新文献

{"title":"Apolipoprotein C-III inhibitors for the treatment of hypertriglyceridemia: a meta-analysis of randomized controlled trials","authors":"Mariana de Moura de Souza ,&nbsp;Beatriz Ximenes Mendes ,&nbsp;Maria Luiza Rodrigues Defante ,&nbsp;Beatriz Austregélio de Athayde de Hollanda Morais ,&nbsp;Otávio Cosendey Martins ,&nbsp;Vitória Martins Prizão ,&nbsp;Gabriela Romaniello","doi":"10.1016/j.metabol.2025.156187","DOIUrl":"10.1016/j.metabol.2025.156187","url":null,"abstract":"<div><h3>Introduction</h3><div>Hypertriglyceridemia is related to atherosclerotic cardiovascular risk and pancreatitis risk. The efficacy and safety of apolipoprotein C-III (APOC-III) inhibitors remains unclear.</div></div><div><h3>Aim</h3><div>To investigate the effects of APOC-III inhibitors on hypertriglyceridemia and its complications.</div></div><div><h3>Methods</h3><div>We systematically searched PubMed, Embase, and Cochrane Central databases from inception to May 2024 for randomized controlled trials (RCTs) comparing APOC-III inhibitors to placebo in patients with hypertriglyceridemia. We pooled percentage standardized mean difference (SMD) changes and risk ratio (RR) for continuous and binary outcomes, respectively, with 95 % confidence interval (CI). Subgroup analyses were performed with APOC-III inhibitors drugs doses (Olezarsen, Volanesorsen and Plozasiran), and primary and secondary hypertriglyceridemia.</div></div><div><h3>Results</h3><div>10 RCTs with 1204 participants were included, of which 46 % were men. APOC-III inhibitors significantly reduced triglycerides (TG) (SMD: −60.56 %; 95 % CI −68.94 to −52.18; p &lt; 0.00001), APOC-III (SMD: −75.44 %; 95 % CI −80.81 to −70.07; p &lt; 0.00001) and non-HDL-c (SMD: −27.49 %; 95 % CI −34.16 to −20.82; p &lt; 0.00001) levels. Consistent results were found for all subgroup analyses. APOC-III inhibitors were capable to normalize TG levels in patients with severe hypertriglyceridemia (RR: 7.92; 95 % CI 4.12 to 15.23; p &lt; 0.00001). There was a significant increase in HDL-c (SMD: 43.92 %; 95 % CI 37.27 to 50.57; p &lt; 0.00001) and LDL-c (SMD: 33.05 %; 95 % CI 9.08 to 57.01; p = 0.007) levels. There was a significant relative risk reduction in acute pancreatitis in the APOC-III inhibitors group (RR 0.17; 95 % CI 0.05 to 0.53; p = 0.007). Adverse events were similar in both groups.</div></div><div><h3>Conclusion</h3><div>APOC-III inhibitors improve TG levels and other lipid panel parameters, as well as reduce episodes of acute pancreatitis in patients with primary and secondary hypertriglyceridemia.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156187"},"PeriodicalIF":10.8,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615493","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":"Arrestin domain containing 3 promotes alcohol-induced liver steatosis by reducing stearoyl-CoA desaturase-1 ubiquitinated degradation","authors":"Ying Tang ,&nbsp;Haoxiong Zhou ,&nbsp;Xuemei Pan,&nbsp;Zhenwei Zhong,&nbsp;Huiling Liu,&nbsp;Yunwei Guo","doi":"10.1016/j.metabol.2025.156175","DOIUrl":"10.1016/j.metabol.2025.156175","url":null,"abstract":"<div><h3>Background and aims</h3><div>Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide with no approved therapy. The development of ALD is strongly associated with hepatic lipid accumulation. Arrestin domain containing 3 (ARRDC3), a member of the α-arrestin family, is involved in obesity, inflammation, and cancer. However, its role in ALD remains largely unexplored.</div></div><div><h3>Methods</h3><div>Both the NIAAA and traditional Lieber-De Carli mouse models of ALD were employed. ARRDC3 expression was evaluated in liver specimens from ALD patients, mouse hepatic tissues, and hepatocytes. Hepatocyte-targeted <em>Arrdc3</em> knockdown was achieved through intrahepatic delivery of adeno-associated virus 8 (AAV8) carrying shRNA under a hepatocyte-specific promoter. Mass spectrometry analysis, immunofluorescence, co-immunoprecipitation (co-IP) assays, and molecular docking were used to identify the interaction between ARRDC3 and stearoyl-CoA desaturase 1 (SCD1).</div></div><div><h3>Results</h3><div>ARRDC3 levels were significantly elevated in the livers of both ALD patients and mouse models. Knockdown of <em>Arrdc3</em> using AAV8 alleviated alcohol-induced liver steatosis in both the NIAAA and traditional Lieber-De Carli mouse models. We demonstrated that ARRDC3 promoted the progression of ALD by inducing lipid accumulation in hepatocytes. Mechanistically, ARRDC3 directly binds to SCD1 and inhibits its ubiquitin-proteasome degradation. Inhibition of SCD1 blocked ARRDC3-induced lipid deposition in hepatocytes. We also observed a correlation between ARRDC3 and SCD1 in liver samples from ALD patients.</div></div><div><h3>Conclusions</h3><div>Our findings reveal that ARRDC3 promotes hepatic steatosis in ALD by reducing the ubiquitin-dependent degradation of SCD1. ARRDC3 may serve as a potential therapeutic target for ALD.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156175"},"PeriodicalIF":10.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143573636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential risk assessment in persons at risk of type 2 diabetes using urinary peptidomics","authors":"Anja Schork ,&nbsp;Andreas Fritsche ,&nbsp;Erwin D. Schleicher ,&nbsp;Andreas Peter ,&nbsp;Martin Heni ,&nbsp;Norbert Stefan ,&nbsp;Reiner Jumpertz von Schwartzenberg ,&nbsp;Martina Guthoff ,&nbsp;Harald Mischak ,&nbsp;Justyna Siwy ,&nbsp;Andreas L. Birkenfeld ,&nbsp;Robert Wagner","doi":"10.1016/j.metabol.2025.156174","DOIUrl":"10.1016/j.metabol.2025.156174","url":null,"abstract":"<div><h3>Objective</h3><div>Individuals at increased risk of type 2 diabetes have recently been classified into six prediabetes clusters, which stratify the risk of progression to diabetes and diabetes complications. Clusters 1, 2 and 4 are low-risk clusters while clusters 3, 5 and 6 are high-risk clusters; individuals in cluster 6 have an elevated risk of nephropathy and all-cause mortality despite delayed onset of diabetes. The urinary peptidome classifiers CKD273 (chronic kidney disease, CKD), HF2 (heart failure, HF) and CAD238 (coronary artery disease, CAD) are based on unique urinary peptide patterns and have shown potential for identifying individuals at risk for CKD and cardiovascular pathologies. This observational study investigates whether peptidome classifiers can differentiate complication risks across the prediabetes clusters and if a novel combination of peptides can distinguish high-risk from low-risk prediabetes clusters.</div></div><div><h3>Methods</h3><div>Urine peptidome analysis was performed on spot urine samples from individuals across 6 prediabetes clusters (<em>n</em> = 249) and 19 individuals with screen-detected diabetes (study cohorts at University Hospital Tübingen, Germany from 11/2004 to 11/2012). Predefined urinary classifiers were calculated for each participant. Lasso regression analysis was used to identify an optimal combination of peptides distinguishing low- Schlesinger et al. (2022), Wagner et al. (2021) [<span><span>1</span></span>,<span><span>2</span></span>,<span><span>4</span></span>] and high-risk (Rooney et al., 2021; Wagner, 2023; Latosinska et al., 2021 [<span><span>3</span></span>,<span><span>5</span></span>,<span><span>6</span></span>]) clusters.</div></div><div><h3>Results</h3><div>The predefined urinary peptidome classifiers CKD273, HF2 and CAD238 differed significantly across prediabetes clusters, particularly with elevated values in cluster 6 compared to the healthiest cluster 2. CKD273, HF2 and CAD238 were inversely associated with insulin sensitivity indexes. Machine Learning identified a combination of 112 urinary peptides that differentiated low-risk from high-risk prediabetes clusters (AUC-ROC 0.868 (95 % CI 0.755–0.981)).</div></div><div><h3>Conclusions</h3><div>Urinary peptidome classifiers support the increased risk of CKD and suggest an elevated risk of heart failure and coronary artery disease in the high-risk prediabetes cluster 6. Urine peptidomics show promising potential as a tool for identifying high-risk prediabetes individuals and guiding early preventive interventions.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156174"},"PeriodicalIF":10.8,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of peroxisomes in the pathogenesis and therapy of renal fibrosis","authors":"Dan Zhang ,&nbsp;Yang-He Zhang ,&nbsp;Bin Liu ,&nbsp;Hong-Xia Yang ,&nbsp;Guang-Tao Li ,&nbsp;Hong-Lan Zhou ,&nbsp;Yi-Shu Wang","doi":"10.1016/j.metabol.2025.156173","DOIUrl":"10.1016/j.metabol.2025.156173","url":null,"abstract":"<div><div>Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes. This comprehensive review systematically elucidates the fundamental biological functions of peroxisomes and delineates the molecular mechanisms underlying peroxisomal dysfunction in renal fibrosis pathogenesis. Here, we discuss the impact of peroxisome dysfunction and pexophagy on oxidative stress, ECM deposition, and renal fibrosis in various cell types including mesangial cells, endothelial cells, podocytes, epithelial cells, and macrophages. Furthermore, this review highlights the recent advancements in peroxisome-targeted therapeutic strategies to alleviate renal fibrosis.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156173"},"PeriodicalIF":10.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492891","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":"Precision nutrition in aging: enhancing frailty prevention through personalized dietary interventions","authors":"Ronal Surya Aditya,&nbsp;Riza Amalia,&nbsp;Rizky Andana Pohan,&nbsp;Ramtia Darma Putri","doi":"10.1016/j.metabol.2025.156172","DOIUrl":"10.1016/j.metabol.2025.156172","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156172"},"PeriodicalIF":10.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483383","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 to: “Precision nutrition in aging: Enhancing frailty prevention through personalized dietary interventions”","authors":"Rosy Conforto ,&nbsp;Valeria Rizzo ,&nbsp;Raffaella Russo ,&nbsp;Elisa Mazza ,&nbsp;Samantha Maurotti ,&nbsp;Carmelo Pujia ,&nbsp;Elena Succurro ,&nbsp;Franco Arturi ,&nbsp;Yvelise Ferro ,&nbsp;Angela Sciacqua ,&nbsp;Arturo Pujia ,&nbsp;Tiziana Montalcini","doi":"10.1016/j.metabol.2025.156171","DOIUrl":"10.1016/j.metabol.2025.156171","url":null,"abstract":"","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156171"},"PeriodicalIF":10.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476741","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":"Ceramides increase mitochondrial permeabilization to trigger mtDNA-dependent inflammation in astrocytes during brain ischemia","authors":"Feng-Qing Huang ,&nbsp;Hong-Fei Wang ,&nbsp;Tong Yang ,&nbsp;Dai Yang ,&nbsp;Peian Liu ,&nbsp;Raphael N. Alolga ,&nbsp;Gaoxiang Ma ,&nbsp;Baolin Liu ,&nbsp;An Pan ,&nbsp;Shi-Jia Liu ,&nbsp;Lian-Wen Qi","doi":"10.1016/j.metabol.2025.156161","DOIUrl":"10.1016/j.metabol.2025.156161","url":null,"abstract":"<div><div>The brain is rich in lipids, and disorders or abnormalities in lipid metabolism can induce neurotoxicity. Ceramides are the central intermediates of sphingolipid metabolism. This study was designed to investigate the potential lipotoxicity of ceramides in brain ischemia. First, a pseudo-targeted lipidomics analysis of plasma samples from stroke patients found significantly elevated levels of long-chain ceramides. A similar observation was made in mice subjected to permanent middle cerebral artery occlusion (pMCAO) surgery. In cultured cells, it was found that the altered ceramides were mainly derived from astrocytes via de novo pathway, and SPTLC2 was a key regulator because <em>Sptlc2</em> knockdown largely blocked ceramide production. Ceramides induced astrocyte activation and triggered oxidative stress to impair mitochondrial homeostasis by increasing mitochondrial permeabilization. Moreover, ceramides triggered the formation of voltage-dependent anion channel (VDAC) oligomers in the mitochondrial outer membrane, through which mtDNA was released into the cytoplasm. Similar to oxygen and glucose depletion treatment, ceramides also increased cGAS activity and STING protein expression. However, this activity was diminished in the presence of the mitochondrial ROS scavenger SKQ1, indicating the involvement of oxidative stress in ceramide action. By facilitating cGAS/STING signaling cascades, ceramides resultantly induced interferon response to aggravate inflammatory damage in the ischemic brain. To address the impact of ceramides on brain ischemic injury in vivo, ceramide generation was blocked in the brain by injection of AAV9-<em>Sptlc2</em> shRNA in pMCAO mice. <em>Sptlc2</em> knockdown in the brain reduced ceramide generation and attenuated brain ischemic damage with astrocyte inactivation. As expected, <em>Sptlc2</em> deficiency effectively blocked cGAS/STING pathway-dependent interferon responses. Together, these findings suggest a new therapeutic strategy for pharmacological intervention to attenuate neuroinflammation.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156161"},"PeriodicalIF":10.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143430152","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":"Neuroprotective effect of small extracellular vesicle-mediated targeting of AMPKα2 in cerebral ischemia","authors":"Alberto Ouro ,&nbsp;Amanda Rodríguez-Díaz ,&nbsp;Tania López-González ,&nbsp;Daniel Romaus-Sanjurjo ,&nbsp;Ánxela Estévez-Salguero ,&nbsp;Ramón Iglesias-Rey ,&nbsp;Mariña Rodríguez-Arrizabalaga ,&nbsp;Paola Fernández-Sanmartín ,&nbsp;Mónica Castro-Mosquera ,&nbsp;Manuel Debasa-Mouce ,&nbsp;Antía Custodia ,&nbsp;Marta Aramburu-Núñez ,&nbsp;María Muñoz-González ,&nbsp;Pablo Aguiar ,&nbsp;Ismael González-García ,&nbsp;Marc Schneeberger ,&nbsp;Rubén Nogueiras ,&nbsp;Carlos Diéguez ,&nbsp;José Castillo ,&nbsp;Tomás Sobrino ,&nbsp;Miguel López","doi":"10.1016/j.metabol.2025.156160","DOIUrl":"10.1016/j.metabol.2025.156160","url":null,"abstract":"<div><h3>Background and aims</h3><div>Smoking is a known risk factor for stroke. However, the ‘stroke paradox’ refers to the observation that stroke patients who smoke often have higher survival rates and better outcomes compared to non-smokers. In this sense, several studies have demonstrated that nicotine (3-[(2<em>S</em>)-1-methylpyrrolidin-2-yl]pyridine) exerts neuroprotective effects. Despite this, the molecular underpinnings of this phenomenon remain unclear. AMP-activated protein kinase (AMPK) is known to play a complex and controversial role in ischemic stroke, with recent evidence suggesting that AMPK inhibition has neuroprotective effects in acute ischemic injury. Nicotine has been shown to influence AMPK signaling in the brain, suppressing appetite and promoting brown fat thermogenesis via hypothalamic AMPK inhibition. Therefore, we hypothesized that the neuroprotective effect of nicotine in ischemia is due to its inhibitory action on AMPK. The aim of this study has been to investigate whether i) AMPK is involved in nicotine's neuroprotective effects on cerebral ischemia and ii) small extracellular vesicle (sEV)-mediated genetic inhibition of AMPK could replicate this effect in rodent models.</div></div><div><h3>Methods</h3><div>Male adult mice or rats subjected to transient middle cerebral artery occlusion (tMCAO) were compared with Sham and/or untreated controls groups. The stroke-induced lesion was evaluated by magnetic resonance imaging (MRI). Nicotine (2 mg/kg/12 h) and the AMPK activator AICAR (500 mg/kg/day) were given subcutaneously upon reperfusion until the end of the follow-up period to tMCAO rats. Control sEVs or sEVs loaded with a plasmid encoding a dominant negative isoform of AMPKα2 (AMPKα2-DN) were administered intravenously twice after reperfusion to tMCAO mice. Molecular pathways were analyzed by western blotting. Bederson and open-field tests were applied to evaluate behavioral parameters.</div></div><div><h3>Results</h3><div>Our MRI findings indicated that nicotine treatment reduced brain ischemic injury and improved neurological recovery, as demonstrated by Bederson test, through the inhibition of brain AMPK in ischemic rats. The AMPK activator AICAR reversed the effect of nicotine on injury size and neurological improvement, indicating that the neuroprotective action was dependent on AMPK inhibition. In addition, treatment with AMPKα2-DN sEVs reduced brain lesion and improved neurological recovery.</div></div><div><h3>Conclusions</h3><div>Our findings demonstrate that the regulation of brain AMPK provides an adequate neuroprotective target for cerebral ischemia, and that the sEV-mediated regulation of this kinase could be a potential clinical strategy against ischemic stroke. Further work, involving scalability in sEV production, immunogenicity, safety and efficacy will be demanding to develop effective and secure therapeutic strategies utilizing sEVs in clinical settings against ischemic stroke.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"167 ","pages":"Article 156160"},"PeriodicalIF":10.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143441496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFT80 and TRPA1 cooperatively regulate bone formation by calcium signaling in response to mechanical stimuli","authors":"Ting Wang ,&nbsp;Yue Chen ,&nbsp;Xinyi Zhu ,&nbsp;Lihe Zheng ,&nbsp;Yingyi Li ,&nbsp;Xiaolei Ruan ,&nbsp;Ziwei Yan ,&nbsp;Zhaolan Guan ,&nbsp;Wen Sun ,&nbsp;Hua Wang","doi":"10.1016/j.metabol.2025.156159","DOIUrl":"10.1016/j.metabol.2025.156159","url":null,"abstract":"<div><h3>Background</h3><div>Intraflagellar transport 80 (IFT80) is vital for primary cilia which can sense and transduce mechanical signals. Mechanical stimuli expedite osteoblastic differentiation and bone formation in mesenchymal stem cells (MSCs). However, how IFT80 regulates mechanical transduction in MSCs remains unclear.</div></div><div><h3>Basic procedure</h3><div>To investigate the role of IFT80 in bone development and mechanical transduction, MSC-specific knock-out IFT80 (Prx1^Cre; IFT80^f/f) mice were generated. These mice exhibited significant skeletal abnormalities. The study further examined the effects of IFT80 deficiency on mechanical stimulation-induced osteoblastic differentiation and bone formation, as well as the underlying molecular mechanisms involving TRPA1 and calcium signaling pathways.</div></div><div><h3>Main findings</h3><div>In our study, Prx1^Cre; IFT80^f/f mice results in pronounced skeletal abnormalities including dwarfism, bone formation defect, malformations in the skull, limbs, and sternum, and abnormal joint structures. Furthermore, IFT80 deficiency in MSCs inhibits mechanical stimulation induced osteoblastic differentiation. Exercise training could not improve the bone formation in Prx1^Cre; IFT80^f/f mice. Mechanistically, IFT80 deficiency in MSCs downregulated the expression of transient receptor potential ankyrin 1 (TRPA1) and TRPA1-mediated Ca²⁺ influx, which further inhibited osteoblastic differentiation under mechanical stimulation by AKT and ERK signaling pathways. Finally, TRPA1 overexpression reversed impaired bone formation in Prx1^Cre; IFT80^f/f mice under exercise training.</div></div><div><h3>Principal conclusions</h3><div>IFT80 and TRPA1 cooperatively regulate osteoblastic differentiation and bone formation in response to mechanical stimulation. These findings suggest that IFT80 and TRPA1 are critical for skeletal homeostasis and may serve as potential therapeutic targets for skeletal disorders.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156159"},"PeriodicalIF":10.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction","authors":"Fadi Khalaf ,&nbsp;Dalia Barayan ,&nbsp;Sean Saldanha ,&nbsp;Marc G. Jeschke","doi":"10.1016/j.metabol.2025.156158","DOIUrl":"10.1016/j.metabol.2025.156158","url":null,"abstract":"<div><div>With age, our metabolic systems undergo significant alterations, which can lead to a cascade of adverse effects that are implicated in both metabolic disorders, such as diabetes, and in the body's ability to respond to acute stress and trauma. To elucidate the metabolic imbalances arising from aging, we introduce the concept of “metabolaging.” This framework encompasses the broad spectrum of metabolic disruptions associated with the hallmarks of aging, including the functional decline of key metabolically active organs, like the adipose tissue. By examining how these organs interact with essential nutrient-sensing pathways, “metabolaging” provides a more comprehensive view of the systemic metabolic imbalances that occur with age. This concept extends to understanding how age-related metabolic disturbances can influence the response to acute stressors, like burn injuries, highlighting the interplay between metabolic dysfunction and the ability to handle severe physiological challenges. Finally, we propose potential interventions that hold promise in mitigating the effects of metabolaging and its downstream consequences.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"166 ","pages":"Article 156158"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143395815","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}