METRNL

更新于：2025-05-07

基本信息

别名

meteorin like, glial cell differentiation regulator、Meteorin-like protein、METRNL

+ [1]

简介

Hormone induced following exercise or cold exposure that promotes energy expenditure. Induced either in the skeletal muscle after exercise or in adipose tissue following cold exposure and is present in the circulation. Able to stimulate energy expenditure associated with the browning of the white fat depots and improves glucose tolerance. Does not promote an increase in a thermogenic gene program via direct action on adipocytes, but acts by stimulating several immune cell subtypes to enter the adipose tissue and activate their prothermogenic actions. Stimulates an eosinophil-dependent increase in IL4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Required for some cold-induced thermogenic responses, suggesting a role in metabolic adaptations to cold temperatures (By similarity).

关联

100 项与 METRNL 相关的临床结果

登录后查看更多信息

100 项与 METRNL 相关的转化医学

登录后查看更多信息

0 项与 METRNL 相关的专利（医药）

登录后查看更多信息

188

项与 METRNL 相关的文献（医药）

2025-12-31·Renal Failure

Higher serum Metrnl levels are associated with increased vascular calcification in hemodialysis patients

Article

作者: Zhang, Aihua ; Ren, Wenwen ; Liu, Conghui

BACKGROUNDMeteorin-like (Metrnl) is a newly identified secreted protein that plays important roles in metabolic and inflammation-related diseases. Our study aimed to evaluate serum Metrnl levels and establish their relationship with vascular calcification (VC) in hemodialysis (HD) patients.METHODSIn total, 313 HD patients and 41 healthy individuals, as controls, were included. Serum levels of Metrnl and other clinical and laboratory parameters were compared. VC was evaluated based on the abdominal aortic calcification (AAC) scores. HD patients were divided into a high-AAC score group (AAC score ≥ 4) and a low-AAC score group (AAC score < 4).RESULTSHD patients had higher serum Metrnl levels than the controls (0.52 ± 0.26 ng/ml vs. 0.24 ± 0.11 ng/ml, p < 0.001). Serum Metrnl concentrations were significantly higher in HD patients in the high-AAC score group than in those in the low-AAC score group (0.55 ± 0.27 vs. 0.49 ± 0.24 ng/ml, p = 0.041). Multivariate logistic regression revealed that serum Metrnl, age, diabetes mellitus, serum total carbon dioxide (tCO₂) and serum intact parathyroid hormone (iPTH) were significant independent determinants of high AAC scores.CONCLUSIONThe results herein provide the first clinical evidence of the association between serum Metrnl and VC in HD patients. Higher Metrnl levels, older age, diabetes mellitus, and higher serum tCO₂ and iPTH levels are independent determining factors for high AAC scores in HD patients.

2025-06-01·Cellular Signalling

Downregulation of miR-410-3p via the METRNL-mediated AMPK/SIRT1/NF-κB signaling axis inhibits oxidative stress and inflammation in idiopathic pulmonary fibrosis

Article

作者: Zhou, Ying ; Gu, Tongjie ; Dong, Zhaoxing ; Zhu, Xiaoxiao ; Wang, Qiong ; Wu, Chunli

Idiopathic pulmonary fibrosis (IPF), a fatal pulmonary condition, is marked by fibrosis and is devoid of efficacious treatments. The aim of our research was to explore the influence of miR-410-3p on the advancement of IPF. For creating a model of lung fibrosis, tracheal injections of 5 mg/kg bleomycin (BLM) were administered to mice, and added 10 ng/mL of TGF-β1 into MRC-5 cell medium. The evaluation of gene and protein expression was conducted using RT-qPCR and western blotting techniques. The assessment of fibrosis in MRC-5 cells and mouse pulmonary tissue involved the use of CCK-8, ELISA, flow cytometry, and HE staining methods. The results of our study revealed a rise in miR-410-3p levels in both TGF-β1-stimulated MRC-5 cells and BLM-exposed mouse pulmonary tissue. Inhibiting miR-410-3p decreased cell viability, lessened oxidative stress (MDA, ROS), decreased levels of inflammatory cytokines (TNF-α, IL-1β, IL-6), curtailed fibrosis-associated proteins (α-SMA, Collagen I, Collagen III, FN1), and amplified the expression of SOD and E-cadherin. The treatment effectively reduced cell fibrosis and improved lung tissue health, thus hindering the advancement of IPF. Mechanically, knocking down miR-410-3p activates AMPK/SIRT1 molecular axis to inhibit NF-κB signaling by up-regulating METRNL expression, thereby inhibiting oxidative stress and inflammation levels, and ultimately improving IPF. In summary, our research indicates that focusing on miR-410-3p might be an effective approach in IPF treatment.

2025-04-01·European Journal of Clinical Investigation

Meteorin‐like protein plasma levels are associated with worse outcomes in de novo heart failure

Article

作者: Feijóo‐Bandín, Sandra ; Lago, Francisca ; Aragón‐Herrera, Alana ; Seoane‐Blanco, Ana ; Bellas, Carlos Tilves ; Morán‐Fernández, Laura ; Agra, Rosa M. ; González‐Juanatey, José R. ; Anido‐Varela, Laura ; Álvarez, Ezequiel ; Vázquez‐Abuín, Xocas ; Solé‐González, Eduard ; Martínez‐Sellés, Manuel ; González‐Maestro, Adrián ; Guerra‐Ramos, José María ; García‐Vega, David ; Carrasquer, Anna ; Portolés, Manuel ; Eiras, Sonia ; Moure‐González, María ; Rodríguez‐Penas, Diego ; Moraña‐Fernández, Sandra ; Roselló‐Lletí, Esther ; Tarazón, Estefanía ; Seijas‐Amigo, Jose ; García‐Seara, Javier

AbstractBackground and AimsMeteorin‐like protein (Metrnl) has been recently suggested as a new adipokine with protective cardiovascular effects. Its circulating levels in patients seem to be associated with heart failure (HF), although with contradictory results. Our aim was to ascertain whether this adipokine could estimate the prognosis of HF in de novo HF (DNHF) patients.MethodsMetrnl plasma levels of 400 patients hospitalized with DNHF (55% of patients with HF with reduced ejection fraction, 17.3% HF with mid‐range ejection fraction, 27.8% HF with preserved ejection fraction) were measured by enzyme‐linked immunosorbent assay. We performed both sex‐pooled and sex‐specific analyses. A 12‐month follow‐up was conducted, during which clinical outcomes such as all‐cause mortality, cardiovascular death and re‐hospitalization due to HF were collected.ResultsAfter a 12‐month follow up, higher plasma Metrnl levels were associated with an increased risk for all‐cause death and cardiovascular death after adjusting by sex, age, LVEF, hypertension, diabetes, ischemic aetiology, chronic renal failure, NT‐proBNP and troponin (hazard ratio [HR] = 1.003, 95% confidence interval [CI] = 1.000–1.005; p‐value<.05 and HR = 1.004, 95% CI = 1.001–1.007, p‐value<.05, respectively). In line with this, DNHF patients with increased levels of circulating Metrnl had a higher number of occurrences of cardiovascular events. Regarding Metrnl associations with parameters implicated in the development and progression of HF, we found that Metrnl circulating levels were positively correlated with age (r = .322, p‐value<.0001), NT‐proBNP (r = .281, p‐value<.0001) and with the renal dysfunction markers urea (r = .322, p‐value<.0001) and creatinine (r = .353, p‐value<.0001) and higher in women than men (473.7 [385.9–594.0] pg/mL vs. 428.7 [349.1–561.3] pg/mL, p‐value<.006). Finally, concerning the subtype of HF, Metrnl plasma levels were higher in HF with preserved ejection fraction.ConclusionPatients with higher Metrnl levels have a worse prognosis in DNHF. Our results reinforce the association of Metrnl plasma levels with HF progression and outcomes.

项与 METRNL 相关的新闻（医药）

2024-08-26

·生物探索

Immunity | 细胞因子METRNL可通过破坏线粒体功能抑制CD8+T细胞抗肿瘤活性

引言逆转肿瘤浸润淋巴细胞（Tumor-infiltrating lymphocyte, TIL）功能衰退是许多癌症免疫治疗策略的重点，但人们对引发和维持TIL功能减退的条件及其可逆性知之甚少。镍纹蛋白样蛋白（METRNL）是一种因运动或寒冷暴露而分泌的细胞因子，可改善葡萄糖耐量，诱导与米色脂肪产热相关的基因表达，并刺激脂肪组织巨噬细胞的替代激活【1, 2】。METRNL通过AMP激活蛋白激酶（AMPK）或过氧化物酶体增殖物激活受体（PPARδ）【3】增加脂肪酸氧化相关基因和抗炎基因的表达，并通过PPARγ改善胰岛素敏感性【4】。METRNL也由M2极化巨噬细胞分泌在屏障组织中，最近的研究表明巨噬细胞分泌的METRNL可以抑制慢性炎症并促进骨骼和心肌修复【5, 6】，但METRNL是否以及如何在T细胞生物学中发挥作用从未被报道。近日，约翰·霍普金斯大学医学院的Michael Lim团队在Immunity杂志上发表了文章The cytokine Meteorin-like inhibits anti-tumor CD8+ T cell responses by disrupting mitochondrial function，他们证明METRN是肿瘤微环境（TME）中免疫细胞分泌的一种代谢活性细胞因子，可促进TME中TIL功能减退。从机制上讲，METRNL增加了PPARδ活性，导致线粒体去极化和氧化磷酸化减少，从而引发CD8+T细胞代谢向糖酵解转变，其敲除或下调则能改善CD8+T细胞代谢并延缓肿瘤生长，证实靶向METRNL-E2F-PPARδ途径以支持TME中CD8+T细胞功能的治疗潜力。该团队首先对从未经治疗的胶质母细胞瘤（GBM）、前列腺癌（PRAD）、膀胱尿路上皮癌（PRAD）和肾细胞癌（RCC）患者中分离出的TIL和外周血单核细胞（PBMC）进行RNA-seq分析，将METRNL确定所有四种肿瘤类型共有的CD8+TIL和PBMC之间显示出差异表达的基因。随后，他们将分泌METRNL的CD8+T细胞与幼稚CD8+T细胞共培养，发现可引起增殖减少，若利用siRNA抑制Metrnl表达，则能减缓小鼠体内肿瘤进展。除了肿瘤浸润CD8+T细胞外，他们进一步分析了PRAD浸润免疫细胞的单细胞测序数据，确认单核/巨噬细胞和树突状细胞也会表达METRNL，且自分泌和旁分泌信号传导均可对CD8+TIL产生抑制作用。功能障碍线粒体的积累是CD8+TIL特征之一，已知METRNL可调节葡萄糖耐量和线粒体电子传递链等多种代谢过程，于是该团队用线粒体膜电位染料TMRM和示踪染料MitoTracker测定METRNL暴露后T细胞中线粒体结构完整性，结果显示T细胞中MitoTracker染色呈剂量依赖性减少且膜电位遭到破坏，这些变化直接导致ROS累积、DNA双链断裂以及细胞凋亡增加。为进一步了解由此引起的代谢变化，他们在高剂量METRNL暴露后对CD8+T细胞的代谢物进行了液相色谱-质谱分析，与对照组间差异最明显的代谢途径与糖酵解有关，暴露组的糖酵解产物增加。接下来，他们比较了WT和Metrn1-/-CD8+T细胞的差异表达基因，观察到编码T细胞效应细胞因子（Gzma/f/g）、炎症细胞因子（Il-10/13/24/4/5等）、趋化因子受体（Ccr1、Cxcr1）的基因在Metrn1-/-CD8+T细胞中上调。为识别METRNL下游的转录因子，他们使用ISMARA工具重新分析上述RNA-seq数据，发现最显著的差异存在于E2F中，之前的工作已报道E2F、PPARδ和METRNL在缓解骨骼肌胰岛素抵抗中的联系【3】，他们测试了METRNL处理后CD8+T细胞中PPARδ的转录及活性，一方面METRNL处理增加了PPARD表达，但该效果在加入E2F泛抑制剂后被消除，另一方面，他们发现在WT CD8+T细胞中加入PPARδ拮抗剂后，细胞中线粒体呼吸能力呈剂量依赖性增加，提示METRNL通过CD8+T细胞中的E2F-PPARd途径对线粒体呼吸产生影响。模式图（Credit: Immunity）综上，这项工作证明细胞因子METRNL是CD8+T细胞代谢的可逆调节因子，可促进肿瘤微环境中TIL功能减退，因此，可通过靶向METRNL-E2F-PPARδ轴来支持CD8+TIL线粒体功能以发挥抗肿瘤活性。参考文献 1. Li, Z.-Y., Zheng, S.-L., Wang, P., Xu, T.-Y., Guan, Y.-F., Zhang, Y.-J., and Miao, C.-Y. (2014). Subfatin is a novel adipokine and unlike Meteorin in adipose and brain expression. CNS Neurosci. Ther. 20, 344–354. 2. Rao, R.R., Long, J.Z., White, J.P., Svensson, K.J., Lou, J., Lokurkar, I.,Jedrychowski, M.P., Ruas, J.L., Wrann, C.D., Lo, J.C., et al. (2014). Meteorin-like is a hormone that regulates immune-adipose interactionsto increase beige fat thermogenesis. Cell 157, 1279–1291. 3. Jung, T.W., Lee, S.H., Kim, H.C., Bang, J.S., Abd El-Aty, A.M.,Hacımuft € uo € glu, A., Shin, Y.K., and Jeong, J.H. (2018). METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARd-dependent pathways in skeletal muscle of mice. Exp. Mol. Med.50, 1–11. 4. Li, Z.-Y., Song, J., Zheng, S.-L., Fan, M.-B., Guan, Y.-F., Qu, Y., Xu, J.,Wang, P., and Miao, C.-Y. (2015). Adipocyte Metrnl Antagonizes Insulin Resistance Through PPARg Signaling. Diabetes 64, 4011–4022. 5. Reboll, M.R., Klede, S., Taft, M.H., Cai, C.L., Field, L.J., Lavine, K.J.,Koenig, A.L., Fleischauer, J., Meyer, J., Schambach, A., et al. (2022).Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase. Science 376, 1343–1347. 6. Baht, G.S., Bareja, A., Lee, D.E., Rao, R.R., Huang, R., Huebner, J.L.,Bartlett, D.B., Hart, C.R., Gibson, J.R., Lanza, I.R., et al. (2020).Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1mechanism. Nat. Metab. 2, 278–289. https://doi.org/10.1016/j.immuni.2024.07.003 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法

2024-08-07

·奇点网

找到关键，那么，复活吧，我的T细胞！

*仅供医学专业人士阅读参考平时在体内威风八面的CD8+T细胞，到了肿瘤微环境里就会各种萎靡不振，奇点糕都觉得它们有点像纸老虎了，但为了抗击要命的癌症，还是得想办法让CD8+T细胞们重振雄风，从代谢角度入手就是当前科学界探索的重点方向。而在营养物质不足的肿瘤微环境里，CD8+T细胞不仅要面对癌细胞极具侵略性的竞争，自身的代谢功能也不见得能保住啊。今天，斯坦福大学与约翰·霍普金斯大学研究者们在Immunity期刊上发表的研究成果，就揭示了导致CD8+T细胞代谢功能异常的重要机制：浸润到肿瘤后被慢性反复刺激的CD8+T细胞，会因自分泌和旁分泌通路分泌一种名为METRNL（中文名为神经胶质细胞分化调节因子样因子）的细胞因子，导致自身“发动机”——线粒体功能异常，代谢功能由此减弱！METRNL的出现，就相当于线粒体这个细胞“发动机”里进了“异物”，它会通过增强转录因子E2F-过氧化物酶体增殖物活化受体δ（PPARδ）调节轴的活性，加剧线粒体去极化并使其氧化磷酸化功能下降，使CD8+T细胞被迫代偿性转向以糖酵解供能，因此想办法去除METRNL这个异物，就能改善CD8+T细胞的代谢状态，使它们更高效地抗癌[1]。论文核心内容总结相信绝大多数读者和奇点糕一样，都不怎么熟悉这次研究的主角“异物”METRNL，这里就先简单说说，METRNL直到2014年才被科学界发现，其正常的生理功能包括促进白色脂肪棕色化[2]、缓解由脂质代谢导致的慢性炎症、增强胰岛素敏感性等等，总之更多出现在代谢相关领域当中，此前跟CD8+T细胞真沾不上边，最多也只是和巨噬细胞有些瓜葛。而斯坦福大学与约翰·霍普金斯大学团队把METRNL揪出来的方法，则是对比胶质母细胞瘤（GBM）、前列腺癌、尿路上皮癌和肾细胞癌患者体内，CD8+肿瘤浸润淋巴细胞（TILs）和CD8+外周血单个核细胞（PBMCs）中表达差异显著的基因，再把范围缩小到存在PD-1、LAG-3和TIM-3三个往往提示CD8+T细胞功能低下的免疫检查点分子（三阳性）的细胞。为了确保结果足够严谨，研究者们还结合了CD8+TILs在肿瘤内的空间分布模式，进一步缩小筛选范围；这样筛选下来之后，只剩下Metrnl和趋化因子受体CXCR6两个基因，与CD8+TILs的三阳性即功能低下有关，而外部单细胞数据集资料又显示，METRNL表达水平最高的就是耗竭和耗竭前的T细胞，那不研究你，研究谁呢？METRNL在浸润到肿瘤微环境、且功能低下的T细胞中表达显著上调实验转移到小鼠模型上后，研究者们首先发现CD8+TILs的METRNL分泌水平与免疫检查点分子表达（即PD-1、LAG-3和TIM-3）正相关，但METRNL的表达上调与PD-1等耗竭相关标志物表达上调“节奏”并不完全一致，反而是在慢性刺激T细胞受体（TCR）信号的作用下，METRNL的表达上调得更明显。而敲除肿瘤模型小鼠的Metrnl，确实可立竿见影地改善CD8+TILs的增殖活性和抑癌效应，延长荷瘤小鼠的生存时间，且肿瘤微环境中的CD8+TILs是主要通过旁分泌通路分泌METRNL；如果外源性补充METRNL，CD8+TILs的各方面能力就会直线下降，且能明显观察到线粒体的去极化和代谢活性减弱；进一步的各项检测则明确证实，METRNL的存在会使CD8+TILs的线粒体呼吸功能下降，而糖酵解供能会相应地代偿性增加。METRNL会使CD8+TILs的线粒体呼吸功能下降，糖酵解供能代偿性增加转录组学分析则显示，METRNL对CD8+TILs功能的负面影响，在机制上与既往已经阐明的，各种导致T细胞功能低下的作用机制都不相同，所以需要单独分析它的下游信号因子及作用机制，研究者们也基于转录组学分析，把转录因子E2F-PPARδ的调节轴给找了出来，以它们作为精准干预靶点，就能让被METRNL“祸害”的CD8+TILs脱离苦海。参考文献：[1]Jackson C M, Pant A, Dinalankara W, et al. The cytokine Meteorin-like inhibits anti-tumor CD8+ Tcell responses by disrupting mitochondrial function[J]. Immunity, 2024. [2]Rao R R, Long J Z, White J P, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis[J]. Cell, 2014, 157(6): 1279-1291.本文作者丨谭硕

临床1期细胞疗法免疫疗法

2023-05-29

·生物谷

Cancer Cell：何川/罗成等发现抑制YTHDF2可增强放疗的抗肿瘤疗效

目前，50-60%的癌症患者采用放射治疗（Radiation Therapy，RT），尽管技术和治疗方法不断改进，但很多患者由于耐药或转移而导致治疗失败。放射增敏治疗策略一般集中在抑制DNA修复或增加目前，50-60%的癌症患者采用放射治疗（Radiation Therapy，RT），尽管技术和治疗方法不断改进，但很多患者由于耐药或转移而导致治疗失败。放射增敏治疗策略一般集中在抑制DNA修复或增加DNA损伤上，其中免疫环境对治愈性至关重要。临床前数据表明，电离辐射（Ionizing Radiation，IR）单独或联合免疫检查点阻断具有免疫刺激作用。基于此，越来越多的临床试验启动免疫检查点阻断与IR联合疗法。然而，目前治疗效果有限，放疗联合免疫检查点疗法的协同作用机制及两者之间的相互关系仍需进一步探索。 N6-甲基腺苷（m6A）是真核生物中最常见的mRNA的修饰，主要调控mRNA的稳定性和翻译效率。m6A主要由RNA甲基转移酶（writer）—METTL3/METTL14、RNA去甲基化酶（eraser）—FTO和ALKBH5动态调控，随后由“阅读子”（reader）—YTHDF1/2/3和YTHDC1/2识别调节RNA代谢。研究表明，YTHDF2参与调控多种生物学过程，包括细胞周期进程，应激反应等，并与多种肿瘤生长有关。然而，YTHDF2在免疫细胞中的调控作用，尤其是在放疗和免疫治疗中的作用尚未被深入探讨。 2023年5月25日，芝加哥大学 Ralph Weichselbaum 教授、何川教授、Hua Laura Liang 教授与中国科学院上海药物研究所罗成研究员等在 Cancer Cell 期刊发表了题为：YTHDF2 inhibition potentiates radiotherapy anti-tumor efficacy 的研究论文。该研究发现，YTHDF2可作为放疗和放疗/免疫联合疗法的潜在靶点，提出了通过抑制YTHDF2来增强临床放射治疗效果的新策略。该研究发现，电离辐射（IR）在小鼠模型和人体内均可诱导免疫抑制性MDSC扩增和YTHDF2表达。IR介导放疗后，表达YTHDF2的MDSC群体增加，这与放疗后的转移进展有关。因此，研究人员猜想YTHDF2的增加是影响放疗效果的原因。于是，研究人员通过构建Ythdf2敲除小鼠模型，发现IR后，Ythdf2的缺失可改变MDSC分化，抑制MDSC向肿瘤转运，并减弱其抑制功能，增强了抗肿瘤免疫，从而增强了局部肿瘤IR的功效。进一步，研究人员发现，IR诱导的YTHDF2表达上调主要依赖于NF-κB/RELA信号通路。反过来，上调的YTHDF2通过直接结合并降解编码NF-κB信号负调控因子（Adrb2、Metrnl和Smpdl3b）的转录本，导致NF-κB活化，从而形成 IR-YTHDF2-NF-κB回路。这些都表明，可以通过抑制YTHDF2来提高抗肿瘤免疫和放疗效果，其有望成为临床放射治疗的新策略。为了进一步证明YTHDF2是潜在的改善放疗和RT/免疫联合疗法的靶点，研究人员通过靶向YTHDF2开展化学干预研究。基于建立的化合物高通量筛选方法，开展了小分子抑制剂的筛选并获得了YTHDF2的活性化合物DC-Y13。通过结构改造获得了化合物DC-Y13-27，其可以在体外直接结YTHDF2蛋白并抑制其与m6A-RNA的结合。此外，DC-Y13-27在小鼠上与敲除YTHDF2类似，不仅可有效提高的IR疗效，而且提高了IR与PD-L1抗体联合治疗的抗肿瘤效果。抑制YTHDF2克服了MDSC诱导的免疫抑制，不仅可以改善局部肿瘤治疗效果，还可以抑制肿瘤转移。

放射疗法免疫疗法信使RNA临床结果