Metabolism: clinical and experimental最新文献_第6页

Effect of GLP-1 receptor agonists and co-agonists on atrial fibrillation risk in overweight or obesity: systematic review and meta-analysis of randomized controlled trials GLP-1受体激动剂和协同激动剂对超重或肥胖患者房颤风险的影响：随机对照试验的系统评价和荟萃分析

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-12-03 DOI: 10.1016/j.metabol.2025.156463

Paschalis Karakasis , Konstantinos Vlachos , Antonios P. Antoniadis , Konstantinos C. Siontis , Dimitrios Patoulias , Nikolaos Fragakis , Christos S. Mantzoros

Background and aims

Overweight and obesity represent major modifiable determinants of atrial fibrillation (AF) incidence and arrhythmia outcomes after AF ablation therapy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and their next-generation co-agonists exert potent weight-lowering and cardiometabolic effects and may therefore confer antiarrhythmic effects. This meta-analysis aimed to quantitatively assess the effect of GLP-1–based therapies on the risk of AF among individuals with overweight or obesity.

Methods

A systematic search of Medline, Scopus, and the Cochrane Library was conducted for randomized controlled trials (RCTs) through October 29, 2025. Data were analyzed using random-effects pairwise meta-analysis.

Results

Twenty-four RCTs encompassing 40,694 participants were included. Compared with placebo, treatment with GLP-1RAs or co-agonists resulted in a 18 % relative reduction in AF risk (Risk Ratio = 0.82; 95 % confidence interval, 0.70–0.96; P = 0.012; I² = 0 %). No significant between-subgroup differences were observed according to agent type (single-, dual-, or triple-receptor agonists), individual compound, baseline BMI category (overweight/obesity vs. obesity alone), diabetes inclusion criteria, trial design [cardiovascular outcomes trial (CVOT) vs. non-CVOT], or administration route (oral vs. subcutaneous). Meta-regression analyses identified no significant effect modification by the magnitude of weight reduction or concomitant SGLT2 inhibitor use.

Conclusions

Among individuals with overweight or obesity, GLP-1RAs and co-agonists were associated with a lower risk of incident AF event. This cardioprotective benefit may, at least in part, operate independently of the magnitude of weight loss.

背景和目的：超重和肥胖是房颤（AF）发病率和房颤消融治疗后心律失常结局的主要可改变决定因素。胰高血糖素样肽-1受体激动剂（GLP-1RAs）及其下一代协同激动剂具有有效的减肥和心脏代谢作用，因此可能具有抗心律失常作用。本荟萃分析旨在定量评估基于glp -1的治疗对超重或肥胖人群房颤风险的影响。方法系统检索截至2025年10月29日的Medline、Scopus和Cochrane图书馆的随机对照试验（RCTs）。数据分析采用随机效应两两荟萃分析。结果共纳入24项随机对照试验，共40,694名受试者。与安慰剂相比，GLP-1RAs或协同激动剂治疗导致AF风险相对降低18%（风险比= 0.82；95%可信区间，0.70-0.96;P = 0.012; I2 = 0%）。根据药物类型（单受体、双受体或三受体激动剂）、单个化合物、基线BMI类别（超重/肥胖vs单独肥胖）、糖尿病纳入标准、试验设计[心血管结局试验（CVOT） vs非CVOT]或给药途径（口服vs皮下），亚组间未观察到显著差异。meta回归分析发现，体重减轻的幅度或同时使用SGLT2抑制剂没有显著的效果改变。结论：在超重或肥胖人群中，GLP-1RAs和协同激动剂与AF事件发生风险较低相关。这种保护心脏的好处，至少在一定程度上，可能与体重减轻的程度无关。

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引用次数: 0

HDL dysfunction: a role in the pathogenesis of cardiometabolic syndrome in chronic HIV infection? HDL功能障碍：在慢性HIV感染的心脏代谢综合征发病机制中的作用？

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-12 DOI: 10.1016/j.metabol.2025.156432

Konstantinos Markakis , Leila Fotooh Abadi , Arnaud Kombe Kombe , Martinos Christodoulides , Theodoros Kelesidis

People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral treatment (ART) have an increased risk of atherosclerotic cardiovascular disease (CVD) and metabolic syndrome (combinations of adiposity, insulin resistance, hypertension, and dyslipidemia). Together, CVD and metabolic syndrome constitute the cardiometabolic syndrome. Traditional CVD risk factors and high-density lipoproteins (HDL) alterations seem to contribute to the elevated CVD risk. Cumulative evidence suggests that assessing HDL function instead of HDL cholesterol levels (HDL-C) may be a better way to assess cardiometabolic risk. In HIV infection, HIV-1, ART, and the altered function of organs like the liver, gastrointestinal tract, and immune system affect the proteome, lipidome, and metabolism of HDL, ultimately leading to its dysfunction. However, the impact of altered HDL functions on PLWH remains unclear and whether HDL dysfunction reflects and/or contributes to cardiometabolic syndrome in HIV infection (bidirectional cross talk regarding how HDL function impacts the cardiometabolic syndrome and vice versa). Large cohorts of PLWH with variable CVD risk using independent assays of HDL function are needed to elucidate the bidirectional crosstalk between HDL functions and cardiometabolic syndrome. Developing novel treatments to improve HDL function in PLWH may have multiple beneficial results, reducing chronic inflammation and cardiometabolic risk in PLWH. This review aims to summarize the scientific evidence related to the role of HDL functions in HIV and how therapeutic targeting of HDL dysfunction may contribute to reduced cardiometabolic risk in PLWH.

接受抗逆转录病毒治疗（ART）的人类免疫缺陷病毒（HIV）（PLWH）感染者患动脉粥样硬化性心血管疾病（CVD）和代谢综合征（肥胖、胰岛素抵抗、高血压和血脂异常的组合）的风险增加。心血管疾病和代谢综合征共同构成心脏代谢综合征。传统的心血管疾病危险因素和高密度脂蛋白（HDL）的改变似乎有助于心血管疾病风险的升高。累积的证据表明，评估高密度脂蛋白功能而不是高密度脂蛋白胆固醇水平（HDL- c）可能是评估心脏代谢风险的更好方法。在HIV感染中，HIV-1、ART以及肝脏、胃肠道和免疫系统等器官功能的改变会影响HDL的蛋白质组、脂质组和代谢，最终导致其功能障碍。然而，HDL功能改变对PLWH的影响尚不清楚，以及HDL功能障碍是否反映和/或促成了HIV感染中的心脏代谢综合征（关于HDL功能如何影响心脏代谢综合征，反之亦然的双向串扰）。需要对具有可变CVD风险的PLWH进行大型队列研究，使用HDL功能的独立分析来阐明HDL功能与心脏代谢综合征之间的双向串扰。开发新的治疗方法来改善PLWH中的HDL功能可能有多种有益的结果，减少PLWH中的慢性炎症和心脏代谢风险。本综述旨在总结与HDL功能在HIV中的作用相关的科学证据，以及如何靶向治疗HDL功能障碍有助于降低PLWH患者的心脏代谢风险。

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引用次数: 0

GLP-1RAs and tirzepatide may reduce heart failure risk in obese but not in non-obese patients with cardiovascular or renal disease: A systematic review and meta-analysis GLP-1RAs和替西肽可以降低肥胖患者的心力衰竭风险，但不能降低心血管或肾脏疾病的非肥胖患者的心力衰竭风险：一项系统回顾和荟萃分析

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-08 DOI: 10.1016/j.metabol.2025.156433

Ju Zhang , Xiangfeng Guan , Mowei Kong , Meng Xia , Yang Yu , Chunxiang Zhang

Background

Cardiovascular disease (CVD) and chronic kidney disease (CKD) frequently coexist, with obesity and type 2 diabetes (T2D) being major contributors to adverse outcomes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and tirzepatide have shown cardiorenal benefits beyond glycemic control, but their efficacy across metabolic phenotypes remains unclear.

Methods

This review was prospectively registered in PROSPERO (CRD420251088042). PubMed, Embase, Web of Science, and Cochrane Library were searched (January 2015–July 2025) for RCTs comparing GLP-1RAs or tirzepatide with placebo in patients with cardiovascular or renal disease. Subgroup analyses were performed according to T2D and obesity status.

Results

A total of 18 RCTs (n = 97,800) involving eight GLP-1RAs and tirzepatide were included, primarily enrolling patients with established cardiovascular or renal disease. GLP-1RAs significantly reduced the risk of the primary composite outcome (RR 0.88, 95 % CI 0.84–0.91, P < 0.001). GLP-1RAs and tirzepatide also significantly reduced the risk of death from any cause (RR 0.88, 95 % CI 0.84–0.92, P < 0.001), and death from cardiovascular causes (RR 0.88, 95 % CI 0.83–0.93, P < 0.001). Although the overall effect of GLP-1RAs on hospitalization for heart failure was not statistically significant (RR 0.92, 95 % CI 0.78–1.08), a potential benefit was observed in obese patients (P for interaction = 0.02), warranting further investigation. GLP-1RAs showed favorable overall safety profile, with a lower incidence of serious adverse events (RR 0.93, 95 % CI 0.89–0.99, P = 0.01) and cardiac adverse events (RR 0.90, 95 % CI 0.85–0.96, P < 0.01) compared with placebo.

Conclusion

In patients with cardiovascular or renal disease, GLP-1RAs and tirzepatide provide consistent cardiovascular and renal protection, with a possible benefit in reducing hospitalization for heart failure among individuals with obesity.

背景：心血管疾病（CVD）和慢性肾脏疾病（CKD）经常共存，肥胖和2型糖尿病（T2D）是导致不良结局的主要因素。胰高血糖素样肽-1受体激动剂（GLP-1RAs）和替西肽已显示出除血糖控制外的心脏肾脏益处，但它们在代谢表型中的功效尚不清楚。方法：本综述在PROSPERO （CRD420251088042）前瞻性注册。检索PubMed， Embase， Web of Science和Cochrane Library（2015年1月- 2025年7月），比较GLP-1RAs或替西肽与安慰剂在心血管或肾脏疾病患者中的作用。根据T2D和肥胖状况进行亚组分析。结果：共纳入18项随机对照试验（n = 97,800），涉及8个GLP-1RAs和替西帕肽，主要纳入已确诊的心血管或肾脏疾病患者。GLP-1RAs显著降低了主要复合结局的风险（RR 0.88, 95 % CI 0.84-0.91, P ）结论：在心血管或肾脏疾病患者中，GLP-1RAs和替西肽提供一致的心血管和肾脏保护，可能有利于减少肥胖患者因心力衰竭住院治疗。

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引用次数: 0

Corrigendum to “Addressing the role of 11β-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model” [Metab Clin Exp 119 (2021) 154749 1–14 [METABOLISM-D-20-01502R3]] “解决11β-羟基类固醇脱氢酶1型在多囊卵巢综合征发展中的作用及其在临床前模型中的选择性抑制的推测治疗效果”[Metab clinical Exp 119 (2021) 154749 1-14] [METABOLISM-D-20-01502R3]。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-15 DOI: 10.1016/j.metabol.2025.156437

Xinyu Li , Shuanggang Hu , Qinling Zhu , Guangxin Yao , Jufang Yao , Jiaxing Li , Yuan Wang , Ying Ding , Jia Qi , Rui Xu , Hanting Zhao , Zhenyi Zhu , Yanzhi Du , Kang Sun , Yun Sun

引用次数: 0

FAM83A acts as an amplifier for lipogenic signaling to facilitate the pathogenesis of metabolic dysfunction-associated steatohepatitis FAM83A作为脂肪生成信号的放大器，促进代谢功能障碍相关脂肪性肝炎的发病机制。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-12-01 DOI: 10.1016/j.metabol.2025.156462

Yang Zhou , Yuhang Dai , Mengyao Qin , Yecheng Li , Lunan Shi , Hao Chen , Hui Fan , Yunli Yu , Le Guo , Jing Xiong

Background & aims

Metabolic dysfunction-associated fatty liver disease (MAFLD) and its more severe manifestation, metabolic-associated steatohepatitis (MASH), are intimately linked to disturbances in lipid metabolism. Although downstream signaling pathways of epidermal growth factor receptor (EGFR), including extracellular signal-regulated kinase (ERK) and proto-oncogene serine/threonine kinase (RAF1), exhibited heightened activation during MASH progression, their specific roles and underlying mechanisms in driving MASH pathogenesis remain inadequately elucidated.

Methods

A comprehensive transcriptomic analysis was performed to indentify key genes involved in MAFLD development. Murine models with hepatocyte-specific depletion or overexpression of FAM83A were subjected to either a high-fat diet (HFD) for 8 or 14 weeks to simulate simple steatosis (MAFL) and MASH, respectively, or a choline-deficient high-fat diet (CDAHFD) to accelerate MASH progression.

Results

FAM83A, recognized as a downstream effector of EGFR that activates the ERK signaling pathway, was predominantly expressed in hepatoctyes and upregulated during MASH pathogenesis in both animal models and clinical patients. Hepatocyte-specific FAM83A knockout delayed MASH progression and mitigated hepatic inflammation and fibrosis. Conversely, overexpression of FAM83A exacerbated MASH pathology, evidence by increased lipid accumulation, inflammation and fibrosis. Mechanistically, insulin induces transcriptional expression of FAM83A, which physically bound to RAF1, enhancing its phosphorylation and subsequent ERK signaling activation. Furthermore, FAM83A-mediated upregulatation of lipogenic gene expression and lipogenesis was significantly inhibited by the treatment of RAF1 inhibitor sorafenib or ERK inhibitor PD98059.

Conclusions

FAM83A promotes MASH pathogenesis by interacting with RAF1 to activate ERK signaling, thereby stimulating fatty acid and cholesterol biosynthesis. Targeting this axis may offer therapeutic potential for MASH and metabolic dyslipidemia.

背景与目的：代谢功能障碍相关脂肪性肝病（MAFLD）及其更严重的表现，代谢相关脂肪性肝炎（MASH），与脂质代谢紊乱密切相关。尽管表皮生长因子受体（EGFR）的下游信号通路，包括细胞外信号调节激酶（ERK）和原癌基因丝氨酸/苏氨酸激酶（RAF1），在MASH进展过程中表现出高度激活，但它们在驱动MASH发病机制中的具体作用和潜在机制仍未充分阐明。方法：通过全面的转录组学分析，鉴定参与MAFLD发展的关键基因。具有肝细胞特异性缺失或FAM83A过表达的小鼠模型分别接受8或14 周的高脂肪饮食（HFD）来模拟单纯性脂肪变性（MAFL）和MASH，或接受缺乏胆碱的高脂肪饮食（CDAHFD）来加速MASH进展。结果：FAM83A被认为是EGFR的下游效应因子，激活ERK信号通路，在动物模型和临床患者中，FAM83A主要在肝细胞中表达，并在MASH发病过程中上调。肝细胞特异性FAM83A敲除延迟了MASH进展，减轻了肝脏炎症和纤维化。相反，FAM83A的过表达加重了MASH病理，证据是脂质积累、炎症和纤维化增加。在机制上，FAM83A物理地与RAF1结合，增强其磷酸化和随后的ERK信号激活。此外，fam83a介导的增脂基因表达上调和脂肪生成被RAF1抑制剂索拉非尼或ERK抑制剂PD98059显著抑制。结论：FAM83A通过与RAF1相互作用激活ERK信号，促进MASH发病机制，从而刺激脂肪酸和胆固醇的生物合成。以该轴为靶点可能为治疗MASH和代谢性血脂异常提供治疗潜力。

{"title":"FAM83A acts as an amplifier for lipogenic signaling to facilitate the pathogenesis of metabolic dysfunction-associated steatohepatitis","authors":"Yang Zhou , Yuhang Dai , Mengyao Qin , Yecheng Li , Lunan Shi , Hao Chen , Hui Fan , Yunli Yu , Le Guo , Jing Xiong","doi":"10.1016/j.metabol.2025.156462","DOIUrl":"10.1016/j.metabol.2025.156462","url":null,"abstract":"<div><h3>Background & aims</h3><div>Metabolic dysfunction-associated fatty liver disease (MAFLD) and its more severe manifestation, metabolic-associated steatohepatitis (MASH), are intimately linked to disturbances in lipid metabolism. Although downstream signaling pathways of epidermal growth factor receptor (EGFR), including extracellular signal-regulated kinase (ERK) and proto-oncogene serine/threonine kinase (RAF1), exhibited heightened activation during MASH progression, their specific roles and underlying mechanisms in driving MASH pathogenesis remain inadequately elucidated.</div></div><div><h3>Methods</h3><div>A comprehensive transcriptomic analysis was performed to indentify key genes involved in MAFLD development. Murine models with hepatocyte-specific depletion or overexpression of FAM83A were subjected to either a high-fat diet (HFD) for 8 or 14 weeks to simulate simple steatosis (MAFL) and MASH, respectively, or a choline-deficient high-fat diet (CDAHFD) to accelerate MASH progression.</div></div><div><h3>Results</h3><div>FAM83A, recognized as a downstream effector of EGFR that activates the ERK signaling pathway, was predominantly expressed in hepatoctyes and upregulated during MASH pathogenesis in both animal models and clinical patients. Hepatocyte-specific FAM83A knockout delayed MASH progression and mitigated hepatic inflammation and fibrosis. Conversely, overexpression of FAM83A exacerbated MASH pathology, evidence by increased lipid accumulation, inflammation and fibrosis. Mechanistically, insulin induces transcriptional expression of FAM83A, which physically bound to RAF1, enhancing its phosphorylation and subsequent ERK signaling activation. Furthermore, FAM83A-mediated upregulatation of lipogenic gene expression and lipogenesis was significantly inhibited by the treatment of RAF1 inhibitor sorafenib or ERK inhibitor PD98059.</div></div><div><h3>Conclusions</h3><div>FAM83A promotes MASH pathogenesis by interacting with RAF1 to activate ERK signaling, thereby stimulating fatty acid and cholesterol biosynthesis. Targeting this axis may offer therapeutic potential for MASH and metabolic dyslipidemia.</div></div>","PeriodicalId":18694,"journal":{"name":"Metabolism: clinical and experimental","volume":"175 ","pages":"Article 156462"},"PeriodicalIF":11.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668954","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}

引用次数: 0

Emerging roles of arginine metabolism in skeletal health and disease 精氨酸代谢在骨骼健康和疾病中的新作用

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-19 DOI: 10.1016/j.metabol.2025.156451

Sibo Wang , Qian Ren , Yansheng Huang , Yibo Ma , Xuefang Zhang , Yuan Liu , Baorong He , Liang Yan

Arginine, as a semi-essential amino acid, plays a pivotal role in bone metabolism and orthopedic diseases. Beyond its function in protein synthesis, arginine serves as a crucial precursor for Nitric Oxide (NO), polyamines, and proline, profoundly influencing osteoblast differentiation, osteoclast activation, immune responses, and angiogenesis. Research indicates that abnormalities in arginine metabolism—such as imbalances in NO synthase activity, upregulation of arginase, or abnormal expression of protein arginine methyltransferases—are closely associated with the onset and progression of osteoporosis, rheumatoid arthritis, osteoarthritis, and bone tumors. Simultaneously, the arginine pathway intertwines with oxidative stress, inflammatory responses, and epigenetic regulation, forming a complex “metabolism-immunity-bone” network. In materials science, arginine has been integrated into various biomaterial systems, including Poly (lactic-co-glycolic acid) (PLGA) scaffolds, chitosan hydrogels, hydroxyapatite composites, and RGD-functionalized polymers, significantly enhancing osteogenic, angiogenic, and immunomodulatory capabilities. Despite ongoing research advancements, challenges persist in understanding the environment-dependent effects of arginine, optimizing dosage, and achieving clinical translation. This review systematically summarizes the mechanistic roles of arginine in bone metabolism regulation and its application progress in engineered materials, offering novel therapeutic insights and research directions for preventing and treating diseases such as osteoporosis, arthritis, and bone tumors.

精氨酸作为一种半必需氨基酸，在骨代谢和骨科疾病中起着关键作用。除了在蛋白质合成中的功能外，精氨酸还是一氧化氮（NO）、多胺和脯氨酸的重要前体，深刻影响成骨细胞分化、破骨细胞活化、免疫反应和血管生成。研究表明，精氨酸代谢异常（如NO合成酶活性失衡、精氨酸酶上调或蛋白精氨酸甲基转移酶表达异常）与骨质疏松症、类风湿关节炎、骨关节炎和骨肿瘤的发生和发展密切相关。同时，精氨酸途径与氧化应激、炎症反应和表观遗传调控交织在一起，形成了一个复杂的“代谢-免疫-骨”网络。在材料科学中，精氨酸已被整合到各种生物材料系统中，包括聚乳酸-羟基乙酸（PLGA）支架、壳聚糖水凝胶、羟基磷灰石复合材料和rgd功能化聚合物，显著增强了成骨、血管生成和免疫调节能力。尽管研究不断取得进展，但在了解精氨酸的环境依赖效应、优化剂量和实现临床转化方面仍然存在挑战。本文系统综述了精氨酸在骨代谢调节中的机制作用及其在工程材料中的应用进展，为骨质疏松症、关节炎、骨肿瘤等疾病的防治提供新的治疗思路和研究方向。

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引用次数: 0

Targeting lipid metabolism in neurodegenerative diseases: From experimental to clinical 针对神经退行性疾病的脂质代谢：从实验到临床。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-12 DOI: 10.1016/j.metabol.2025.156436

Junpeng Long , Shasha Liu , Yaning Shi , Chanjuan Zhang , Li Qin , Qidi Ai

The human brain, despite accounting for only 2 % of total body weight, exhibits an exceptionally high lipid content (approximately 20 % of its mass), highlighting the critical role of lipid metabolism in maintaining neural homeostasis and function. Neurodegenerative diseases—including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)—are characterized by progressive neuronal dysfunction and myelin degeneration. These conditions predominantly affect aging populations and represent a growing global health challenge. While aging remains the primary risk factor, compelling evidence now underscores the involvement of dysregulated lipid metabolism in their pathogenesis. However, the precise mechanisms linking dynamic lipid metabolic alterations to disease progression remain incompletely elucidated. This review systematically examines the multifaceted contributions of lipid metabolism to neurodegenerative processes and critically assesses emerging therapeutic strategies that target lipid pathways for the treatment of neurodegenerative disorders.

人脑，尽管只占总体重的2% %，却显示出异常高的脂质含量（约占其质量的20% %），突出了脂质代谢在维持神经稳态和功能中的关键作用。神经退行性疾病——包括阿尔茨海默病（AD）、帕金森病（PD）、中风、亨廷顿病（HD）和肌萎缩侧索硬化症（ALS）——以进行性神经元功能障碍和髓鞘变性为特征。这些疾病主要影响老龄人口，并构成日益严重的全球卫生挑战。虽然衰老仍然是主要的危险因素，但令人信服的证据强调了脂质代谢失调在其发病机制中的作用。然而，将动态脂质代谢改变与疾病进展联系起来的确切机制仍未完全阐明。本综述系统地考察了脂质代谢对神经退行性过程的多方面贡献，并批判性地评估了针对脂质途径治疗神经退行性疾病的新兴治疗策略。

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引用次数: 0

Metabolic reprogramming in diabetic foot ulcers: mechanisms, therapeutic implications and future perspectives 糖尿病足溃疡的代谢重编程：机制、治疗意义和未来展望。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-22 DOI: 10.1016/j.metabol.2025.156455

Li Jinyi , Ding Xianguang , Ding Yuhan , Huang Haoyue , Xia Zhongyu , Wang Lianhui , Jianda Xu

As a devastating complication, diabetic foot ulcer (DFU) is characterized by chronic, nonhealing wounds due to vasculopathy and neuropathy. It has emerged as a most challenging chronic disease worldwide, affecting millions of people worldwide. The higher mortality and disability rates urgently require innovative therapeutic strategies. Recently, different from nanotechnology, metabolic reprogramming is believed to be associated with the occurrence and progression of various diseases (including cancer, obesity and neurodegenerative diseases). They can alter their cellular metabolism (involving glucose, lipid, and amino acid metabolism) to cope with different external stimuli and pressures. As a novel potential strategy, metabolic reprogramming also exhibits great potential to improve the wound healing of DFU. This review aims to summarize the current knowledge, biological characteristics, and underlying mechanisms of metabolic reprogramming in DFU. And we propose their potential therapeutic implications to improve wound healing and prevent complications in DFU. In addition, we also highlight the current challenges and the future perspectives.

作为一种毁灭性的并发症，糖尿病足溃疡（DFU）的特点是由血管病变和神经病变引起的慢性，不愈合的伤口。它已成为全世界最具挑战性的慢性病，影响着全世界数百万人。较高的死亡率和残疾率迫切需要创新的治疗策略。最近，与纳米技术不同，代谢重编程被认为与各种疾病（包括癌症、肥胖和神经退行性疾病）的发生和进展有关。它们可以改变细胞代谢（包括葡萄糖、脂质和氨基酸代谢）以应对不同的外部刺激和压力。作为一种新的潜在策略，代谢重编程在促进DFU创面愈合方面也显示出巨大的潜力。本文综述了DFU中代谢重编程的相关知识、生物学特性和潜在机制。我们提出了它们在改善DFU伤口愈合和预防并发症方面的潜在治疗意义。此外，我们还强调了当前的挑战和未来的展望。

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引用次数: 0

Induction of Yin Yang 1 (YY1) overexpression in mature adipocytes promotes dysfunctional adipose tissue and systemic insulin resistance in mice 诱导成熟脂肪细胞中阴阳1 （YY1）过表达可促进小鼠脂肪组织功能失调和全身胰岛素抵抗。

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-19 DOI: 10.1016/j.metabol.2025.156439

Line Pedersen , Christy M. Gliniak , Thomas Myhre Dale , Qingzhang Zhu , Chao Li , Jan-Bernd Funcke , Clair Crewe , Jiahui Luo , Lauren Palluth , Yi Zhu , Philipp E. Scherer

The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced weight gain, systemic insulin resistance, and increased liver steatosis in comparison to control littermates. In contrast, brown adipose tissue-specific YY1 overexpression has little effect on mice fed a high-fat diet. In an obesogenic environment, acute ectopic adiponectin promoter-driven YY1 expression promotes weight loss, cell death, and adipose tissue inflammation. Underlying the observed reduction in adipose tissue mass, we find that YY1 controls gene networks related to adipose tissue expansion, lipid anabolic pathways (hypertrophy), and hyperplasia (adipogenesis). Taken together, our results demonstrate novel roles of Yy1 in white adipose tissue. This versatile transcription factor regulates central aspects of white adipose tissue biology that are essential for maintaining whole-body physiology.

无所不在的转录因子盈阳1 （YY1）在多种生物过程中起着重要作用，据信可调节高达10% %的人类基因。在产热棕色脂肪组织中，YY1与控制线粒体基因表达、调节细胞氧化呼吸、防止饮食引起的肥胖和能量平衡改变有关。另一方面，YY1在非产热的白色脂肪组织中的作用在很大程度上仍然未知。在这里，我们发现脂肪细胞特异性诱导YY1促进小鼠功能失调的脂肪组织和全身性胰岛素抵抗。与对照组相比，成熟脂肪细胞中YY1的长期诱导导致体重增加减少、全身胰岛素抵抗和肝脏脂肪变性增加。相比之下，棕色脂肪组织特异性YY1过表达对喂食高脂肪饮食的小鼠几乎没有影响。在致胖环境中，急性异位脂联素启动子驱动的YY1表达促进体重减轻、细胞死亡和脂肪组织炎症。在观察到的脂肪组织质量减少的基础上，我们发现YY1控制着与脂肪组织扩张、脂质合成代谢途径（肥大）和增生（脂肪生成）相关的基因网络。综上所述，我们的结果证明了Yy1在白色脂肪组织中的新作用。这种多功能转录因子调节白色脂肪组织生物学的中心方面，对维持全身生理至关重要。

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引用次数: 0

Imeglimin ameliorates MASLD by targeting PEN2 to activate AMPK pathway imimimin通过靶向PEN2激活AMPK通路来改善MASLD

IF 11.9 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Metabolism: clinical and experimental

Pub Date : 2026-02-01 Epub Date: 2025-11-25 DOI: 10.1016/j.metabol.2025.156458

Jinghe Li , Ruizhong Zhang , Xin Zeng , Weilong Xu , Ling Gao , Shuyun He , Bingbing Wu , Yanjie Ma , Yunzhong Nie , Jun Shirakawa , Huimin Xia , Wei Li

Background and Aims

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent and increasingly chronic liver disorder with increasing global incidence, closely linked to prolonged high-fat diet (HFD)-induced metabolic impairment. Although imeglimin, an antidiabetic agent known to improve insulin resistance, has demonstrated therapeutic potential in metabolic diseases, its effects and underlying molecular mechanism in MASLD remain unclear.

Approach and results

In this study, we employed a long-term (48-week) high-fat diet-induced murine model of MASLD to recapitulate human disease progression, then treated those mice with imeglimin for 6 months to investigate its therapeutic effects. Imeglimin treatment improved insulin resistance, restored liver function, attenuated hepatic inflammation, and promoted hepatocyte viability. PEN2, a component of the γ-secretase complex, is identified as the key target of imeglimin. The therapeutic effects of imeglimin are abrogated in liver-specific Pen2-deficient mice or upon pharmacologic inhibition of AMP-activated protein kinase (AMPK), indicating that activation of PEN2-AMPK signaling is required for its beneficial effects. Furthermore, we found that imeglimin also protected human pluripotent stem cell (hPSC)-derived hepatocyte-like cells from free fatty acid (FFA)-induced lipid accumulation.

Conclusion

Collectively, our findings indicate that imeglimin ameliorates hepatic lipotoxicity by targeting PEN2 to activate AMPK axis, suggesting its potential as a new drug for MASLD treatment in the near future.

背景和目的代谢功能障碍相关脂肪变性肝病（MASLD）是一种高度普遍且日益增长的慢性肝病，全球发病率不断上升，与长期高脂肪饮食（HFD）引起的代谢损伤密切相关。尽管已知可改善胰岛素抵抗的抗糖尿病药物伊米明已被证明在代谢性疾病中具有治疗潜力，但其在MASLD中的作用和潜在的分子机制尚不清楚。方法和结果在本研究中，我们采用长期（48周）高脂肪饮食诱导的MASLD小鼠模型来概括人类疾病的进展，然后用伊米霉素治疗这些小鼠6个月，观察其治疗效果。依米霉素治疗可改善胰岛素抵抗，恢复肝功能，减轻肝脏炎症，促进肝细胞活力。PEN2是γ-分泌酶复合物的一个组成部分，被认为是imimimin的关键靶点。在肝脏特异性的pen2缺陷小鼠或amp活化蛋白激酶（AMPK）的药理学抑制下，伊米霉素的治疗作用被取消，这表明其有益作用需要激活PEN2-AMPK信号。此外，我们发现伊米明还能保护人类多能干细胞（hPSC）衍生的肝细胞样细胞免受游离脂肪酸（FFA）诱导的脂质积累。综上所述，我们的研究结果表明，伊梅米明通过靶向PEN2激活AMPK轴来改善肝脂毒性，表明其在不久的将来可能成为治疗MASLD的新药。

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