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Advances in Clinical Medicine
Vol. 13  No. 12 ( 2023 ), Article ID: 78237 , 10 pages
10.12677/ACM.2023.13122830

鸢尾素在肥胖及相关代谢性疾病中的 研究进展

张怡宁1,2，尹晓1,2*

1山东大学齐鲁医学院，山东 济南

2济南市中心医院代谢性疾病中心，山东 济南

收稿日期：2023年11月27日；录用日期：2023年12月21日；发布日期：2023年12月28日

摘要

目前肥胖及相关代谢性疾病在全球呈持续流行的态势，已成为严重的公共卫生问题。鸢尾素是运动期间由骨骼肌分泌产生的肌源性细胞因子，通过多种信号通路改善肥胖及代谢异常。本文对鸢尾素与肥胖及相关代谢性疾病的关系进行综述，主要包括2型糖尿病、动脉粥样硬化性心血管疾病、非酒精性脂肪性肝病和骨质疏松症，旨在阐明鸢尾素在代谢靶器官中的调控机制，为肥胖及相关代谢性疾病探索新的治疗途径。

关键词

鸢尾素，肥胖症，2型糖尿病，动脉粥样硬化性心血管疾病，非酒精性脂肪性肝病，骨质疏松症

Research Progress of Irisin in Obesity and Related Metabolic Diseases

Yining Zhang1,2, Xiao Yin1,2*

1Cheeloo College of Medicine, Shandong University, Jinan Shandong

2Metabolic Disease Center, Jinan Central Hospital, Jinan Shandong

Received: Nov. 27th, 2023; accepted: Dec. 21st, 2023; published: Dec. 28th, 2023

ABSTRACT

Obesity and related metabolic diseases are continuously epidemic worldwide and have become a serious public health problem. Irisin, a myokine produced by skeletal muscle during exercise, ameliorates obesity and metabolic abnormalities through multiple signal pathways. This paper reviews the relationship between irisin with obesity and related metabolic diseases, including type 2 diabetes, atherosclerotic cardiovascular disease, non-alcoholic fatty liver disease and osteoporosis, with the aim of clarifying the regulatory mechanisms of irisin in metabolic target organs and exploring new therapeutic pathways for obesity and related metabolic diseases.

Keywords:Irisin, Obesity, Type 2 Diabetes, Atherosclerotic Cardiovascular Disease, Non-Alcoholic Fatty Liver Disease, Osteoporosis

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 鸢尾素概述

1.1. 鸢尾素结构和分布特点

鸢尾素于2012年首次被发现，是运动期间骨骼肌分泌的一种肌源性细胞因子，由其前体III型纤维连接蛋白结构域包含蛋白5 (fibronectin type III domain containing 5, FNDC5)在细胞膜上经蛋白酶水解剪切而来，这一过程受到过氧化物酶增殖物激活受体γ共刺激因子1α (peroxisome proliferator-activated receptor γ coactivator-1α, PGC-1α)调控 [1] 。鸢尾素通常以同型二聚体的形式存在 [2] ，在体内分布广泛，骨骼肌、心脏、肺、肝脏、脾、胃肠、肾脏、脂肪组织、脑组织、卵巢、睾丸等部位均有FNDC5基因表达，骨骼肌是鸢尾素的主要来源 [3] [4] [5] 。

运动可以促进骨骼肌细胞以PGC-1α依赖的方式增加FNDC5的表达并提高血浆鸢尾素水平 [6] 。质谱分析法(mass spectrometry, MS)检测有氧运动人群血浆鸢尾素水平约为4.3 ng/mL，而久坐、活动量较少的人群中血浆鸢尾素水平约为3.6 ng/mL [7] 。运动对血浆鸢尾素的影响与运动类型、强度和持续时间有关，短期高强度运动可显著提高鸢尾素水平 [8] 。血浆鸢尾素水平有昼夜节律，峰值时间约为夜间9点，清晨6点左右降至低谷值，但鸢尾素水平不受膳食影响 [9] 。

酶联免疫吸附测定(enzyme linked immunosorbent assay, ELISA)和MS技术均可用于检测血浆鸢尾素。ELISA试剂盒测定人体的血浆鸢尾素数值不稳定，从110 ng/mL [5] 到9 μg/mL [10] 不等。MS是检测血浆蛋白质浓度的“金标准”，此方法检测人体血浆鸢尾素参考值为3~5 ng/mL [7] ，在小鼠体内为0.3 ng/mL [11] 。

1.2. 鸢尾素受体

鸢尾素作用于机体不同器官组织的受体尚未确定。Kim等人提出整合素αV (integrin αV)可能是鸢尾素在脂肪和骨细胞上的受体 [11] [12] [13] 。鸢尾素也作用于人类肺部、微血管内皮细胞 [14] 和脂肪组织间充质干细胞 [15] 上的integrin αV受体。一项关于脂肪祖细胞(adipocytes progenitor cells, APC)的研究发现，鸢尾素可以与CD81、integrin αV/β1和integrin αV/β5受体形成复合物，通过激活黏附斑激酶(focal adhesion kinase, FAK)调节APC向棕色脂肪细胞分化 [16] 。integrin αV也被发现是鸢尾素在肠上皮细胞的功能性受体 [17] 。目前不能排除鸢尾素与其他受体结合的可能性，明确鸢尾素特异性受体可以帮助我们深入探究其作用机制及生物学效应。

2. 鸢尾素与肥胖及相关代谢性疾病

肥胖症(obesity)是体内脂肪过度储积和体重异常的一种慢性代谢性疾病，常并发2型糖尿病(type 2 diabetes mellitus, T2DM)、非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)、动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease, ASCVD)、高血压、代谢性骨病、多囊卵巢综合征和痛风等一系列疾病，已成为严重的全球性公共健康问题。根据《中国居民营养与慢性病状况报告(2020年)》的数据，我国已有6亿超重和肥胖人群，居世界首位 [18] 。肥胖症是遗传和环境共同作用的多基因疾病 [19] ，缺乏有效治疗手段。研究发现鸢尾素通过多种途径改善机体代谢异常，本文重点论述鸢尾素与肥胖症、T2DM、ASCVD、NAFLD和骨质疏松症的关系，以期为肥胖及相关代谢性疾病的治疗提供新的干预靶点。

2.1. 鸢尾素与肥胖症

2.1.1. 鸢尾素促进脂肪细胞棕色化

脂肪组织功能是肥胖症研究的重要内容。脂肪组织分为白色脂肪组织(white adipose tissue, WAT)和棕色脂肪组织(brown adipose tissue, BAT)两种完全不同的类型。WAT以甘油三酯(triglyceride, TG)的形式储存能量；而BAT富含线粒体，高表达棕色脂肪细胞特异性解偶联蛋白1 (uncoupling protein1, UCP1)，通过解偶联方式释放热能，可以减轻体重并改善代谢 [20] 。

鸢尾素可以激活p62/核因子E2相关因子2 (nuclear factor erythroid 2-related factor 2, Nrf2)/血红素氧合酶-1 (hemeoxygenase-1, HO-1)通路，上调棕色脂肪特异性蛋白PGC-1α、PR结构域蛋白16 (PR domain-containing 16, PRDM16)和UCP1的表达，诱导小鼠皮下脂肪组织“棕色化” [21] 。在细胞水平，鸢尾素抑制人体皮下脂肪组织干细胞的成脂分化 [22] ，但可以通过上调UCP1、PGC-1α促进皮下脂肪组织中白色脂肪细胞向米色脂肪细胞转化 [23] 。没有发现鸢尾素在内脏脂肪组织中促进棕色化基因上调的现象 [23] [24] ，这表明鸢尾素对组织的促棕色化作用具有部位依赖性。

2.1.2. 鸢尾素减轻脂肪组织炎症

肥胖患者脂肪组织巨噬细胞积聚产生过多的炎性因子，包括肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)和白介素-18 (interleukin-18, IL-18)等，进而促进全身慢性炎症反应 [25] 。动物实验发现消瘦鼠脂肪组织富含抗炎的M2巨噬细胞，肥胖鼠富含促炎性反应的M1巨噬细胞 [26] ，而鸢尾素可显著降低M1巨噬细胞的Toll样受体4 (toll-like receptor 4, TLR4)和髓样分化主要反应蛋白88 (myeloid differentiation primary response gene 88, MyD88)水平，抑制核因子-κB (nuclear factor-kappa B, NF-κB)磷酸化，从而减少促炎细胞因子的释放 [27] ，改善肥胖症的全身炎症状态。

2.2. 鸢尾素与T2DM

动物研究发现鸢尾素可以改善糖尿病鼠的胰岛素抵抗和糖代谢状态 [28] ，但与人群糖尿病患者血浆鸢尾素水平的研究结论不太一致。多数研究发现T2DM患者较非糖尿病患者血浆鸢尾素水平降低 [29] [30] [31] ，但1型糖尿病(type 1 diabetes mellitus, T1DM)患者血浆鸢尾素水平高于对照组 [32] 。血浆鸢尾素水平还与糖尿病微血管病变发生风险相关。据报道，血浆鸢尾素水平与尿白蛋白排泄率呈负相关关系 [33] ，增殖性视网膜病变患者血浆鸢尾素水平低于无视网膜病变的糖尿病患者 [34] 。

基础研究发现鸢尾素可以通过多种途径改善葡萄糖稳态。首先，鸢尾素可以通过AMP活化蛋白激酶(AMP-activated protein kinase, AMPK)和p38-丝裂原活化蛋白激酶(mitogen activated protein kinase, MAPK)/PGC-1α信号通路促使骨骼肌细胞葡萄糖转运蛋白4 (glucose transporter 4, GLUT4)易位，促进骨骼肌摄取利用葡萄糖 [35] [36] 。人类和小鼠肝细胞的研究均发现鸢尾素通过磷脂酰肌醇3-激酶(phosphoinositide 3-kinase, PI3K)/AKT途径减少肝脏糖异生，促进肝糖原合成 [37] ，同时降低胰岛素抵抗和炎症反应 [38] 。此外，鸢尾素可以激活p38 MAPK/细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)通路促进胰岛β细胞增殖并减少细胞凋亡 [39] ，而且近期研究发现胰岛组织以葡萄糖依赖的方式分泌鸢尾素 [40] 。以上均提示鸢尾素对T2DM具有潜在治疗价值。

2.3. 鸢尾素与ASCVD

多项研究显示ASCVD患者血清鸢尾素水平显著降低 [41] [42] [43] 。日本男性人群的前瞻性研究结果显示血浆鸢尾素水平与冠状动脉钙化(coronary artery calcification, CAC)发生率呈负相关关系 [44] ，补充鸢尾素可以明显改善动脉粥样硬化小鼠的内皮功能障碍、减少动脉斑块面积 [45] ，提示鸢尾素可能改善ASCVD结局。

2.3.1. 鸢尾素改善血管内皮功能障碍

研究显示鸢尾素可以通过ERK信号通路促进内皮细胞增殖，同时上调抗凋亡基因Bcl-2和下调促凋亡基因Bax/caspase的表达，减少细胞凋亡 [46] 。此外，鸢尾素可以激活AKT/雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)/核糖体S6激酶1 (ribosome protein subunit 6 kinase 1, S6K1)/Nrf2通路增加血管内皮细胞活力并刺激新生血管生成 [47] 。内皮祖细胞(endothelial progenitor cells, EPCs)可以促进血管修复和形成 [48] ，而超重/肥胖儿童EPCs的增加与鸢尾素水平升高有关 [49] 。研究发现鸢尾素可以促进EPCs增殖和迁移，协助内皮修复过程 [50] ，但目前机制不清。

异常的内皮依赖性血管舒张(endothelium-dependent vasodilation, EDV)是血管内皮功能障碍的重要标志 [51] ，肥胖导致EDV受损和一氧化氮(nitric oxide, NO)生物利用度降低，增加氧化应激损伤并加速ASCVD进展 [52] 。鸢尾素通过激活AMPK/PI3K/AKT/内皮一氧化氮合酶(endothelin nictric oxide synthase, eNOS)通路改善EDV损伤，减轻小鼠动脉粥样斑块进程 [53] 。此外，鸢尾素可以通过促进超氧化物歧化酶(superoxide dismutase, SOD)、过氧化氢酶-9 (catalase-9, CAT-9)和谷胱甘肽过氧化物酶(glutathione peroxidase, GSH-Px)等关键抗氧化酶的表达，减少氧化应激对血管内皮细胞的损伤 [54] 。

2.3.2. 鸢尾素改善高脂血症

高脂血症ASCVD的主要危险因素。中国肥胖人群血浆鸢尾素水平升高常伴随高密度脂蛋白胆固醇(high density lipid-cholesterol, HDL-C)水平下降 [55] 和低密度脂蛋白胆固醇(low density lipid-cholesterol, LDL-C)水平的升高 [56] 。但欧洲正常体重人群血浆鸢尾素水平与TG、CH、LDL-C含量呈负相关关系 [57] 。

动物研究发现鸢尾素可以通过环磷酸腺苷(cyclic adenosine monophosphate, cAMP)/蛋白激酶A (protein kinase A, PKA)/激素敏感脂酶(hormone-sensitive lipase, HSL)途径降低肥胖鼠CH和游离脂肪酸水平 [58] 。鸢尾素干预可以上调肝脏和肠道中ATP结合盒亚家族G成员5 (ATP binding cassette subfamily G member 5 Gene, ABCG5)/ABCG8表达，增加胆汁胆固醇的转运和粪便胆固醇的输出 [59] ，并通过AMPK抑制甾醇调节元件结合转录因子2 (sterol regulatory element binding protein, SREBP2)减少肝脏胆固醇的产生 [60] 。另外，鸢尾素还通过下调CCAAT增强子结合蛋白α (CCAAT enhancer bindingprotein α, C/EBPα)、PPARγ和脂肪酸结合蛋白基因4 (fatty acid binding protein 4, FABP4)基因的表达抑制脂质合成 [61] 。这些结果表明鸢尾素通过多种途径发挥调脂作用，降低ASCVD风险。

综上所述，鸢尾素参与改善内皮细胞功能、调节血脂等过程延缓ASCVD进展，介导了运动锻炼对心脏的保护作用。

2.4. 鸢尾素与NAFLD

NAFLD是指除外酒精和其他明确的肝损害因素所致的、以肝脏脂肪变性为主要特征的临床病理综合征，现已成为西方国家和我国最常见的肝脏疾病，其主要致病因素包括氧化应激、炎症反应、脂肪毒性、糖毒性、肠源性内毒素和遗传易感性等 [62] 。肥胖、T2DM、高脂血症等均为NAFLD的易感因素 [63] [64] 。研究发现长期运动导或外源补充鸢尾素都可以降低NAFLD发病风险 [65] [66] ，肥胖患者血浆鸢尾素水平与肝脏脂肪含量呈负相关关系 [67] 。

动物实验发现鸢尾素可以抑制小鼠脂肪生成酶活性从而降低肝脏TG含量 [68] ，减少肝脏脂肪变性小鼠的内质网应激 [69] ，细胞实验证实以上效果是通过抑制肝X受体α (liver X receptor-α)和固醇调节元件结合蛋白(sterol regulated element binding protein-1c, SREBP-1c)实现的 [70] 。同时，鸢尾素可以降低乙酰辅酶A羧化酶(acetyl-CoA carboxylase, ACC)和脂肪酸合成酶(fatty acid synthetase, FAS)等成脂基因的表达减少肝脂肪变性，竞争性抑制肝细胞中的骨髓分化因子2 (myeloid differentiation factor 2, MD2)和TLR4的结合，从而发挥抗炎和抗氧化应激的作用 [70] [71] 。动物研究发现基因敲除FNDC5缺乏会加重高脂血症、肝脏脂肪变性，而FNDC5过表达通过调节AMPK/哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTORC1)/PPARα轴有效逆转上述情况 [72] ，由此可见，鸢尾素对NAFLD有多重保护作用。

2.5. 鸢尾素与骨质疏松症

骨质疏松症是一种以骨量降低和骨组织微结构破坏为特征，导致骨脆性增加和易于骨折的代谢性骨病。长期肥胖会造成骨微结构的破坏 [73] ，减少骨形成和骨转换，进而导致骨质疏松及骨折风险增加 [74] 。

肌肉骨骼相互作用是近年来的研究热点，研究显示肌源性细胞因子鸢尾素与骨骼健康状况密切相关。研究显示，运动员血浆鸢尾素水平与骨密度(bone mineral density, BMD)正相关 [75] 。T1DM儿童血浆鸢尾素浓度与骨钙素(osteocalcin, OC)、碱性磷酸酶(alkaline phosphatase, ALP)、I型胶原C端肽(C-terminal telopeptide of type I collagen, CTX)正相关 [76] 。骨折愈合过程中也发现血浆鸢尾素水平增加，表明鸢尾素对骨形成有积极作用，能够促进骨骼健康 [77] 。

骨骼重塑需要成骨细胞和破骨细胞相互协调以维持骨形成和骨吸收的平衡。鸢尾素可以促进成骨细胞分化、抑制破骨细胞分化，从而保护骨骼微结构。研究发现成骨细胞FDNC5条件敲除小鼠出现骨密度降低、骨发育延迟表型，骨组织胶原蛋白1 (collagen 1)、Runt相关转录因子2 (runt-related transcription factor 2, Runx2)等促成骨细胞分化基因表达下调，促破骨细胞分化相关基因表达增加，而注射重组鸢尾素可以逆转上述改变 [78] 。细胞实验也发现鸢尾素可以通过P38 MAPK/ERK信号通路促进啮齿类动物成骨细胞增殖分化 [79] 。此外，利用小鼠骨细胞(MLO-Y4)的研究显示，鸢尾素可以促进ERK1/2磷酸化(p-ERK)和骨细胞分化关键转录因子Atf4的表达抑制细胞凋亡，从而防止骨质流失和骨质疏松症 [80] 。Narayanan等人发现炎症性肠病大鼠伴有严重骨质疏松，鸢尾素可以通过减轻炎症反应发挥骨骼保护作用 [81] 。众所周知，微重力对骨代谢有负面影响 [82] ，注射鸢尾素可改善微重力模型动物的骨量丢失 [83] 。进入模拟太空环境的骨细胞在微重力影响下表现为成骨基因抑制和破骨基因表达升高，而鸢尾素干预可以部分逆转微重力环境的影响 [84] 。

总之，鸢尾素能通过多种途径调节骨代谢平衡，是骨骼代谢中的一个新的关键角色，但仍需寻找更多的临床证据，为鸢尾素在预防和治疗骨质疏松症方面提供依据。

3. 总结与展望

肥胖及相关代谢性疾病患病率逐年上升，造成了巨大的经济压力和社会负担。体育运动可以降低体重、改善代谢，降低多种代谢疾病的风险。鸢尾素是运动产生的肌源性因子，可通过多种途径改善糖脂代谢紊乱，同时改善血管内皮细胞功能及调节骨代谢，也参与减轻机体炎症、氧化应激等过程，在肥胖症和代谢病的诊疗中有一定的临床应用前景。本文综述了鸢尾素在肥胖和相关代谢疾病中的作用及调控机制，为该类疾病的预防和治疗提供了新视角。鸢尾素在器官组织中的特异性受体尚未完全明确，明确鸢尾素的特异性受体及受体后信号通路可以为肥胖症和代谢性疾病的治疗提供潜在药物干预靶点，促进鸢尾素在基础–临床转化应用中的进程。

基金项目

山东省自然科学基金(ZR2021MH204)。

文章引用

张怡宁,尹 晓. 鸢尾素在肥胖及相关代谢性疾病中的研究进展
Research Progress of Irisin in Obesity and Related Metabolic Diseases[J]. 临床医学进展, 2023, 13(12): 20104-20113. https://doi.org/10.12677/ACM.2023.13122830

参考文献

  1. 1. Boström, P., Wu, J., Jedrychowski, M.P., et al. (2012) A PGC1-α-Dependent Myokine That Drives Brown-Fat-Like Development of White Fat and Thermogenesis. Nature, 481, 463-468. https://doi.org/10.1038/nature10777

  2. 2. Panati, K., Narala, V.R., Narasimha, V.R., et al. (2018) Expression, Puri-fication and Biological Characterisation of Recombinant Human Irisin (12.5 kDa). Journal of Genetic Engineering and Biotechnology, 16, 459-466. https://doi.org/10.1016/j.jgeb.2018.06.007

  3. 3. Zhao, R. (2022) Irisin at the Crossroads of Inter-Organ Communi-cations: Challenge and Implications. Frontiers in Endocrinology, 13, Article 989135. https://doi.org/10.3389/fendo.2022.989135

  4. 4. Aydin, S., Kuloglu, T., Aydin, S., et al. (2014) A Comprehensive Immunohistochemical Examination of the Distribution of the Fat-Burning Protein Irisin in Biological Tissues. Peptides, 61, 130-136. https://doi.org/10.1016/j.peptides.2014.09.014

  5. 5. Huh, J.Y., Panagiotou, G., Mougios, V., et al. (2012) FNDC5 and Irisin in Humans: I. Predictors of Circulating Concentrations in Serum and Plasma and II. mRNA Expression and Circulating Concentrations in Response to Weight Loss and Exercise. Metabolism: Clinical and Experimental, 61, 1725-1738. https://doi.org/10.1016/j.metabol.2012.09.002

  6. 6. Perakakis, N., Triantafyllou, G.A., Fernández-Real, J.M., et al. (2017) Physiology and Role of Irisin in Glucose Homeostasis. Nature Reviews Endocrinology, 13, 324-337. https://doi.org/10.1038/nrendo.2016.221

  7. 7. Jedrychowski, M.P., Wrann, C.D., Paulo, J.A., et al. (2015) Detec-tion and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry. Cell Metabolism, 22, 734-740. https://doi.org/10.1016/j.cmet.2015.08.001

  8. 8. Fatouros, I.G. (2018) Is Irisin the New Player in Exercise-Induced Adaptations or Not? A 2017 Update. Clinical Chemistry and Laboratory Medicine, 56, 525-548. https://doi.org/10.1515/cclm-2017-0674

  9. 9. Anastasilakis, A.D., Polyzos, S.A., Saridakis, Z.G., et al. (2014) Circulating Irisin in Healthy, Young Individuals: Day-Night Rhythm, Effects of Food Intake and Exercise, and Associa-tions with Gender, Physical Activity, Diet, and Body Composition. The Journal of Clinical Endocrinology and Metabo-lism, 99, 3247-3255. https://doi.org/10.1210/jc.2014-1367

  10. 10. Bubak, M.P., Heesch, M.W.S., Shute, R.J., et al. (2017) Irisin and Fi-bronectin Type III Domain-Containing 5 Responses to Exercise in Different Environmental Conditions. International Journal of Exercise Science, 10, 666-680.

  11. 11. Kim, H., Wrann, C.D., Jedrychowski, M., et al. (2018) Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors. Cell, 175, 1756-1768.E17. https://doi.org/10.1016/j.cell.2018.10.025

  12. 12. Fu, T., Li, C., Sun, Z., et al. (2022) Integrin αV Mediates the Effects of Irisin on Human Mature Adipocytes. Obesity Facts, 15, 442-450. https://doi.org/10.1159/000523871

  13. 13. Xue, Y., Hu, S., Chen, C., et al. (2022) Myokine Irisin Promotes Osteogenesis by Activating BMP/SMAD Signaling via αV Integrin and Regulates Bone Mass in Mice. International Journal of Biological Sciences, 18, 572-584. https://doi.org/10.7150/ijbs.63505

  14. 14. Bi, J., Zhang, J., Ren, Y., et al. (2020) Exercise Hormone Irisin Mitigates Endothelial Barrier Dysfunction and Microvascular Leakage-Related Diseases. JCI Insight, 5, e136277. https://doi.org/10.1172/jci.insight.136277

  15. 15. Yan, W., Chen, Y., Guo, Y., et al. (2022) Irisin Promotes Cardiac Homing of Intravenously Delivered MSCs and Protects against Ischemic Heart Injury. Advanced Science, 9, e2103697. https://doi.org/10.1002/advs.202103697

  16. 16. Oguri, Y., Shinoda, K., Kim, H., et al. (2020) CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling. Cell, 182, 563-577.E20. https://doi.org/10.1016/j.cell.2020.06.021

  17. 17. Bi, J., Zhang, J., Ren, Y., et al. (2020) Irisin Reverses Intestinal Ep-ithelial Barrier Dysfunction during Intestinal Injury via Binding to the Integrin αVβ5 Receptor. Journal of Cellular and Molecular Medicine, 24, 996-1009. https://doi.org/10.1111/jcmm.14811

  18. 18. Afshin, A., Forouzanfar, M.H., Reitsma, M.B., et al. (2017) Health Ef-fects of Overweight and Obesity in 195 Countries over 25 Years. The New England Journal of Medicine, 377, 13-27. https://doi.org/10.1056/NEJMoa1614362

  19. 19. Cuciureanu, M., Caratașu, C.C., Gabrielian, L., et al. (2023) 360-Degree Perspectives on Obesity. Medicina, 59, Article 1119. https://doi.org/10.3390/medicina59061119

  20. 20. Samuelson, I. and Vidal-Puig, A. (2020) Studying Brown Adipose Tissue in a Human in Vitro Context. Frontiers in Endocrinology, 11, Article 629. https://doi.org/10.3389/fendo.2020.00629

  21. 21. Tsai, Y.C., Wang, C.W., Wen, B.Y., et al. (2020) Involvement of the p62/Nrf2/HO-1 Pathway in the Browning Effect of Irisin in 3T3-L1 Adipocytes. Molecular and Cellular Endocri-nology, 514, Article 110915. https://doi.org/10.1016/j.mce.2020.110915

  22. 22. Huh, J.Y., Dincer, F., Mesfum, E. and Mantzoros, C.S. (2014) Irisin Stimulates Muscle Growth-Related Genes and Regulates Adipocyte Differentiation and Metabolism in Humans. International Journal of Obesity, 38, 1538-1544. https://doi.org/10.1038/ijo.2014.42

  23. 23. Zhang, Y., Xie, C., Wang, H., et al. (2016) Irisin Exerts Dual Effects on Browning and Adipogenesis of Human White Adipocytes. American Journal of Physiology-Endocrinology and Metabo-lism, 311, E530-E541. https://doi.org/10.1152/ajpendo.00094.2016

  24. 24. Li, H., Zhang, Y., Wang, F., et al. (2019) Effects of Irisin on the Differentiation and Browning of Human Visceral White Adipocytes. American Journal of Translational Research, 11, 7410-7421.

  25. 25. Wood, I.S., Wang, B., Jenkins, J.R. and Trayhurn, P. (2005) The Pro-Inflammatory Cytokine IL-18 Is Expressed in Human Adipose Tissue and Strongly Upregulated by TNFα in Human Adipocytes. Biochemical and Bio-physical Research Communications, 337, 42242-42249. https://doi.org/10.1016/j.bbrc.2005.09.068

  26. 26. Lumeng, C.N., Bodzin, J.L. and Saltiel, A.R. (2007) Obesity Induces a Phenotypic Switch in Adipose Tissue Macrophage Polari-zation. The Journal of Clinical Investigation, 117, 175-184. https://doi.org/10.1172/JCI29881

  27. 27. Mazur-Bialy, A.I., Pocheć, E. and Zarawski, M. (2017) Anti-Inflammatory Properties of Irisin, Mediator of Physical Activity, Are Connected with TLR4/MyD88 Signaling Pathway Activation. International Journal of Molecular Sciences, 18, Article 701. https://doi.org/10.3390/ijms18040701

  28. 28. Pang, Y., Zhu, H., Xu, J., et al. (2017) β-Arrestin-2 Is Involved in Irisin Induced Glucose Metabolism in Type 2 Diabetes via p38 MAPK Signaling. Experimental Cell Research, 360, 199-204. https://doi.org/10.1016/j.yexcr.2017.09.006

  29. 29. Liu, J.J., Wong, M.D., Toy, W.C., et al. (2013) Lower Circulating Irisin Is Associated with Type 2 Diabetes Mellitus. Journal of Diabetes and Its Complications, 27, 365-369. https://doi.org/10.1016/j.jdiacomp.2013.03.002

  30. 30. Shoukry, A., Shalaby, S.M., El-Arabi Bdeer, S., et al. (2016) Circulating Serum Irisin Levels in Obesity and Type 2 Diabetes Mellitus. IUBMB Life, 68, 544-556. https://doi.org/10.1002/iub.1511

  31. 31. Huerta-Delgado, A.S., Roffe-Vazquez, D.N., Gonzalez-Gil, A.M., et al. (2020) Serum Irisin Levels, Endothelial Dysfunction, and Inflammation in Pediatric Patients with Type 2 Diabetes Melli-tus and Metabolic Syndrome. Journal of Diabetes Research, 2020, Article ID: 1949415. https://doi.org/10.1155/2020/1949415

  32. 32. Ates, I., Arikan, M.F., Erdogan, K., et al. (2017) Factors Associated with Increased Irisin Levels in the Type 1 Diabetes Mellitus. Endocrine Regulations, 51, 1-7. https://doi.org/10.1515/enr-2017-0001

  33. 33. Wang, H.H., Zhang, X.W., Chen, W.K., et al. (2015) Relationship be-tween Serum Irisin Levels and Urinary Albumin Excretion in Patients with Type 2 Diabetes. Journal of Diabetes and Its Complications, 29, 384-389. https://doi.org/10.1016/j.jdiacomp.2015.01.001

  34. 34. Hu, W., Wang, R., Li, J., et al. (2016) Association of Irisin Concentrations with the Presence of Diabetic Nephropathy and Retinopathy. Annals of Clinical Biochemistry, 53, 67-74. https://doi.org/10.1177/0004563215582072

  35. 35. Xin, C., Liu, J., Zhang, J., et al. (2016) Irisin Improves Fatty Acid Oxidation and Glucose Utilization in Type 2 Diabetes by Regulating the AMPK Signaling Pathway. International Jour-nal of Obesity, 40, 443-451. https://doi.org/10.1038/ijo.2015.199

  36. 36. Ye, X., Shen, Y., Ni, C., et al. (2019) Irisin Reverses Insulin Resistance in C2C12 Cells via the p38-MAPK-PGC-1α Pathway. Peptides, 119, Article ID: 170120. https://doi.org/10.1016/j.peptides.2019.170120

  37. 37. Liu, T.Y., Shi, C.X., Gao, R., et al. (2015) Irisin Inhibits He-patic Gluconeogenesis and Increases Glycogen Synthesis via the PI3K/Akt Pathway in Type 2 Diabetic Mice and Hepatocytes. Clinical Science, 129, 839-850. https://doi.org/10.1042/CS20150009

  38. 38. Zheng, S., Chen, N., Kang, X., et al. (2022) Irisin Alleviates FFA In-duced β-Cell Insulin Resistance and Inflammatory Response through Activating PI3K/AKT/FOXO1 Signaling Pathway. Endocrine, 75, 740-751. https://doi.org/10.1007/s12020-021-02875-y

  39. 39. Liu, S., Du, F., Li, X., et al. (2017) Effects and Underlying Mechanisms of Irisin on the Proliferation and Apoptosis of Pancreatic β Cells. PLOS ONE, 12, e0175498. https://doi.org/10.1371/journal.pone.0175498

  40. 40. Norman, D., Drott, C.J., Carlsson, P.O. and Espes, D. (2022) Irisin-A Pancreatic Islet Hormone. Biomedicines, 10, Article 258. https://doi.org/10.3390/biomedicines10020258

  41. 41. Guo, W., Zhang, B. and Wang, X. (2020) Lower Irisin Levels in Coronary Artery Disease: A Meta-Analysis. Minerva Endocrinologica, 45, 61-69. https://doi.org/10.23736/S0391-1977.17.02663-3

  42. 42. Pan, J.A., Zhang, H., Yu, Q., et al. (2021) Association of Circulating Irisin Levels and the Characteristics and Prognosis of Coronary Artery Disease. The American Journal of the Medical Sciences, 362, 63-71. https://doi.org/10.1016/j.amjms.2021.02.020

  43. 43. Remuzgo-Martínez, S., Rueda-Gotor, J., Pulito-Cueto, V., et al. (2022) Irisin as a Novel Biomarker of Subclinical Atherosclerosis, Cardiovascular Risk and Severe Disease in Axial Spondyloarthritis. Frontiers in Immunology, 13, Article 894171. https://doi.org/10.3389/fimmu.2022.894171

  44. 44. Hisamatsu, T., Miura, K., Arima, H., et al. (2018) Relationship of Serum Irisin Levels to Prevalence and Progression of Coronary Artery Calcification: A Prospective, Population-Based Study. International Journal of Cardiology, 267, 177-182. https://doi.org/10.1016/j.ijcard.2018.05.075

  45. 45. Chen, J., Li, K., Shao, J., et al. (2022) Irisin Suppresses Nicotine-Mediated Atherosclerosis by Attenuating Endothelial Cell Migration, Proliferation, Cell Cycle Arrest, and Cell Senescence. Frontiers in Cardiovascular Medicine, 9, Article 851603. https://doi.org/10.3389/fcvm.2022.851603

  46. 46. Song, H., Wu, F., Zhang, Y., et al. (2014) Irisin Promotes Human Umbilical Vein Endothelial Cell Proliferation through the ERK Signaling Pathway and Partly Suppresses High Glucose-Induced Apoptosis. PLOS ONE, 9, e110273. https://doi.org/10.1371/journal.pone.0110273

  47. 47. Zhang, M., Xu, Y. and Jiang, L. (2019) Irisin Attenuates Oxi-dized Low-Density Lipoprotein Impaired Angiogenesis through AKT/mTOR/S6K1/Nrf2 Pathway. Journal of Cellular Physiology, 234, 18951-18962. https://doi.org/10.1002/jcp.28535

  48. 48. Evans, C.E., Iruela-Arispe, M.L. and Zhao, Y.Y. (2021) Mechanisms of Endothelial Regeneration and Vascular Repair and Their Application to Regenerative Medicine. The American Journal of Pathology, 191, 52-65. https://doi.org/10.1016/j.ajpath.2020.10.001

  49. 49. De Meneck, F., Victorino De Souza, L., Oliveira, V. and do Franco, M.C. (2018) High Irisin Levels in Overweight/Obese Children and Its Positive Correlation with Metabolic Pro-file, Blood Pressure, and Endothelial Progenitor Cells. Nutrition, Metabolism, and Cardiovascular Diseases, 28, 756-764. https://doi.org/10.1016/j.numecd.2018.04.009

  50. 50. Zhu, G., Wang, J., Song, M., et al. (2016) Irisin Increased the Number and Improved the Function of Endothelial Progenitor Cells in Diabetes Mellitus Mice. Journal of Cardiovascu-lar Pharmacology, 68, 67-73. https://doi.org/10.1097/FJC.0000000000000386

  51. 51. Hou, N., Han, F. and Sun, X. (2015) The Relationship be-tween Circulating Irisin Levels and Endothelial Function in Lean and Obese Subjects. Clinical Endocrinology, 83, 339-343. https://doi.org/10.1111/cen.12658

  52. 52. Li, M., Qian, M., Kyler, K. and Xu, J. (2021) Adipose Tis-sue-Endothelial Cell Interactions in Obesity-Induced Endothelial Dysfunction. Frontiers in Cardiovascular Medicine, 8, Article 681581. https://doi.org/10.3389/fcvm.2021.681581

  53. 53. Lu, J., Xiang, G., Liu, M., et al. (2015) Irisin Protects against En-dothelial Injury and Ameliorates Atherosclerosis in Apolipoprotein E-Null Diabetic Mice. Atherosclerosis, 243, 438-448. https://doi.org/10.1016/j.atherosclerosis.2015.10.020

  54. 54. Mazur-Bialy, A.I., Kozlowska, K., Pochec, E., et al. (2018) Myokine Irisin-Induced Protection against Oxidative Stress in vitro. Involvement of Heme Oxygenase-1 and An-tioxidazing Enzymes Superoxide Dismutase-2 and Glutathione Peroxidase. Journal of Physiology and Pharmacology, 69, 117-125.

  55. 55. Park, K.H., Zaichenko, L., Brinkoetter, M., et al. (2013) Circulating Irisin in Relation to Insulin Re-sistance and the Metabolic Syndrome. The Journal of Clinical Endocrinology and Metabolism, 98, 4899-4907. https://doi.org/10.1210/jc.2013-2373

  56. 56. Yang, S., Xiao, F., Pan, L., et al. (2015) Association of Serum Irisin and Body Composition with Chronic Kidney Disease in Obese Chinese Adults: A Cross-Sectional Study. BMC Nephrology, 16, Article No. 16. https://doi.org/10.1186/s12882-015-0009-5

  57. 57. Oelmann, S., Nauck, M., Völzke, H., et al. (2016) Circulating Irisin Concentrations Are Associated with a Favourable Lipid Profile in the General Population. PLOS ONE, 11, e0154319. https://doi.org/10.1371/journal.pone.0154319

  58. 58. Xiong, X.Q., Chen, D., Sun, H.J., et al. (2015) FNDC5 Overexpression and Irisin Ameliorate Glucose/Lipid Metabolic Derangements and Enhance Lipolysis in Obesity. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, 1852, 1867-1875. https://doi.org/10.1016/j.bbadis.2015.06.017

  59. 59. Li, H., Shen, J., Wu, T., et al. (2019) Irisin Is Controlled by Far-nesoid X Receptor and Regulates Cholesterol Homeostasis. Frontiers in Pharmacology, 10, Article 548. https://doi.org/10.3389/fphar.2019.00548

  60. 60. Tang, H., Yu, R., Liu, S., et al. (2016) Irisin Inhibits Hepatic Cho-lesterol Synthesis via AMPK-SREBP2 Signaling. EBioMedicine, 6, 139-148. https://doi.org/10.1016/j.ebiom.2016.02.041

  61. 61. Ma, E.B., Sahar, N.E., Jeong, M. and Huh, J.Y. (2019) Irisin Exerts Inhibitory Effect on Adipogenesis through Regulation of Wnt Signaling. Frontiers in Physiology, 10, Article 1085. https://doi.org/10.3389/fphys.2019.01085

  62. 62. Nassir, F. (2022) NAFLD: Mechanisms, Treatments, and Bi-omarkers. Biomolecules, 12, Article 824. https://doi.org/10.3390/biom12060824

  63. 63. Tilg, H., Adolph, T.E. and Moschen, A.R. (2021) Multiple Parallel Hits Hypothesis in Nonalcoholic Fatty Liver Disease: Revisited after a Decade. Hepatology, 73, 833-842. https://doi.org/10.1002/hep.31518

  64. 64. Cernea, S. and Raz, I. (2021) NAFLD in Type 2 Diabetes Mellitus: Still Many Challenging Questions. Diabetes/Metabolism Research and Reviews, 37, e3386. https://doi.org/10.1002/dmrr.3386

  65. 65. Polyzos, S.A., Kountouras, J., Anastasilakis, A.D., et al. (2014) Irisin in Patients with Nonalcoholic Fatty Liver Disease. Metabolism: Clinical and Experimental, 63, 207-217. https://doi.org/10.1016/j.metabol.2013.09.013

  66. 66. Canivet, C.M., Bonnafous, S., Rousseau, D., et al. (2020) He-patic FNDC5 Is a Potential Local Protective Factor against Non-Alcoholic Fatty Liver. Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, 1866, Article 165705. https://doi.org/10.1016/j.bbadis.2020.165705

  67. 67. Zhang, H.J., Zhang, X.F., Ma, Z.M., et al. (2013) Irisin Is In-versely Associated with Intrahepatic Triglyceride Contents in Obese Adults. Journal of Hepatology, 59, 557-562. https://doi.org/10.1016/j.jhep.2013.04.030

  68. 68. So, W.Y. and Leung, P.S. (2016) Irisin Ameliorates Hepatic Glu-cose/Lipid Metabolism and Enhances Cell Survival in Insulin-Resistant Human HepG2 Cells through Adenosine Mono-phosphate-Activated Protein Kinase Signaling. The International Journal of Biochemistry & Cell Biology, 78, 237-247. https://doi.org/10.1016/j.biocel.2016.07.022

  69. 69. Zhang, J., Ren, Y., Bi, J., et al. (2020) Involvement of Kindlin-2 in Irisin’s Protection against Ischaemia Reperfusion-Induced Liver Injury in High-Fat Diet-Fed Mice. Journal of Cellular and Molecular Medicine, 24, 13081-13092. https://doi.org/10.1111/jcmm.15910

  70. 70. Park, M.J., Kim, D.I., Choi, J.H., et al. (2015) New Role of Irisin in Hepatocytes: The Protective Effect of Hepatic Steatosis in vitro. Cellular Signalling, 27, 1831-1839. https://doi.org/10.1016/j.cellsig.2015.04.010

  71. 71. Zhu, W., Sahar, N.E., Javaid, H.M.A., et al. (2021) Exer-cise-Induced Irisin Decreases Inflammation and Improves NAFLD by Competitive Binding with MD2. Cells, 10, Article 3306. https://doi.org/10.3390/cells10123306

  72. 72. Liu, T.Y., Xiong, X.Q., Ren, X.S., et al. (2016) FNDC5 Allevi-ates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice. Diabetes, 65, 3262-3275. https://doi.org/10.2337/db16-0356

  73. 73. Litwic, A.E., Westbury, L.D., Ward, K., et al. (2021) Adiposity and Bone Microarchitecture in the GLOW Study. Osteoporosis International, 32, 689-698. https://doi.org/10.1007/s00198-020-05603-w

  74. 74. Ali, D., Tencerova, M., Figeac, F., et al. (2022) The Patho-physiology of Osteoporosis in Obesity and Type 2 Diabetes in Aging Women and Men: The Mechanisms and Roles of Increased Bone Marrow Adiposity. Frontiers in Endocrinology, 13, Article 981487. https://doi.org/10.3389/fendo.2022.981487

  75. 75. Colaianni, G., Notarnicola, A., Sanesi, L., et al. (2017) Irisin Lev-els Correlate with Bone Mineral Density in Soccer Players. Journal of Biological Regulators and Homeostatic Agents, 31, 21-28.

  76. 76. Faienza, M.F., Brunetti, G., Sanesi, L., et al. (2018) High Irisin Levels Are Associated with Better Glycemic Control and Bone Health in Children with Type 1 Diabetes. Diabetes Research and Clinical Practice, 141, 10-17. https://doi.org/10.1016/j.diabres.2018.03.046

  77. 77. Serbest, S., Tiftikçi, U., Tosun, H.B. and Kısa, Ü. (2017) The Irisin Hormone Profile and Expression in Human Bone Tissue in the Bone Healing Process in Patients. Medical Science Monitor, 23, 4278-4283. https://doi.org/10.12659/MSM.906293

  78. 78. Zhu, X., Li, X., Wang, X., et al. (2021) Irisin Deficiency Disturbs Bone Metabolism. Journal of Cellular Physiology, 236, 664-676. https://doi.org/10.1002/jcp.29894

  79. 79. Qiao, X., Nie, Y., Ma, Y., et al. (2016) Irisin Promotes Osteoblast Proliferation and Differentiation via Activating the MAP Kinase Signaling Pathways. Scientific Reports, 6, Article No. 18732. https://doi.org/10.1038/srep18732

  80. 80. Storlino, G., Colaianni, G., Sanesi, L., et al. (2020) Irisin Prevents Disuse-Induced Osteocyte Apoptosis. Journal of Bone and Miner-al Research, 35, 766-775. https://doi.org/10.1002/jbmr.3944

  81. 81. Narayanan, S.A., Metzger, C.E., Bloomfield, S.A., et al. (2018) Inflammation-Induced Lymphatic Architecture and Bone Turnover Changes Are Ameliorated by Irisin Treatment in Chronic Inflammatory Bowel Disease. FASEB Journal, 32, 4848-4861. https://doi.org/10.1096/fj.201800178R

  82. 82. Leblanc, A., Matsumoto, T., Jones, J., et al. (2013) Bisphosphonates as a Supplement to Exercise to Protect Bone during Long-Duration Spaceflight. Osteoporosis International, 24, 2105-2114. https://doi.org/10.1007/s00198-012-2243-z

  83. 83. Colaianni, G., Mongelli, T., Cuscito, C., et al. (2017) Irisin Prevents and Restores Bone Loss and Muscle Atrophy in Hind-Limb Suspended Mice. Scientific Reports, 7, Arti-cle No. 2811. https://doi.org/10.1038/s41598-017-02557-8

  84. 84. Colucci, S., Colaianni, G., Brunetti, G., et al. (2020) Irisin Prevents Microgravity-Induced Impairment of Osteoblast Differentiation in Vitro during the Space Flight CRS-14 Mission. FASEB Journal, 34, 10096-10106. https://doi.org/10.1096/fj.202000216R

    85. NOTES

    *通讯作者。

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