科微学术

生物工程学报

2025年4月18日 9:04 星期五
首页 > 过刊浏览>2022年第38卷第1期 >119-129. DOI:10.13345/j.cjb.210290
PDF HTML阅读 XML下载 导出引用 引用提醒
脂肪含量和肥胖相关蛋白介导的mRNA m6A修饰对动物脂肪沉积的作用及其应用前景
作者:
基金项目:

国家自然科学基金(31872979, 31572366)；国家重点研发计划(2017YFD0502002)


The effect of fat mass and obesity associated proteins mediated mRNA m6A modification on animal fat deposition and its application prospects
Author:
  • 摘要
    • | |
  • 访问统计
    • |
  • 参考文献 [56]
    • |
  • 相似文献
    • | | |
  • 文章评论
    摘要:

    在动物脂肪沉积过程中，前体脂肪细胞增殖、分化和脂滴甘油三酯水平的变化受到一系列转录因子和信号通路的调节。目前研究者虽对脂肪形成的转录调控机制进行了深入研究，但对转录后mRNA水平修饰的报道相对较少。甲基化转移酶、去甲基化酶和甲基化阅读蛋白共同调控的mRNA m6A修饰是动态可逆的且与脂肪沉积密切相关。脂肪含量和肥胖相关蛋白(fat mass and obesity associated, FTO) 作为RNA去甲基化酶，影响被修饰基因的表达，在脂肪沉积中起关键作用。文中系统分析并总结了FTO介导的mRNA m6A去甲基化对动物脂肪沉积的作用及分子调控机制的研究进展，提示FTO可能成为有效治疗肥胖症的靶点; 还对近年来研发FTO抑制剂的情况进行了总结，并展望其在治疗肥胖症方面的研究前景。

    Abstract:

    In the process of animal fat deposition, the proliferation and differentiation of pre-adipocytes and the change of lipid droplet content in adipocytes are regulated by a series of transcription factors and signal pathways. Although researchers have conducted in-depth studies on the transcriptional regulation mechanisms of adipogenesis, there are relatively few reports on post-transcriptional modification on mRNA levels. The modification of mRNA m6A regulated by methyltransferase, demethylase and methylation reading protein is a dynamic and reversible process, which is closely related to fat deposition in animals. Fat mass and obesity associated proteins (FTO) act as RNA demethylases that affect the expression of modified genes and play a key role in fat deposition. This article summarized the mechanism of FTO-mediated demethylation of mRNA m6A in the process of animal fat deposition, suggesting that FTO may become a target for effective treatment of obesity. Moreover, this review summarized the development of FTO inhibitors in recent years.

    参考文献
    [1] He C, Zhang QY, Sun HW, et al. Role of miRNA and lncRNA in animal fat deposition-a review. Chin J Biotech, 2020, 36(8): 1504-1514 (in Chinese). 何春, 张琦悦, 孙浩玮, 等. miRNA和lncRNA在动物脂肪沉积中的研究进展. 生物工程学报, 2020, 36(8): 1504-1514.
    [2] Kumar S, Behl T, Sachdeva M, et al. Implicating the effect of ketogenic diet as a preventive measure to obesity and diabetes mellitus. Life Sci, 2021, 264: 118661.
    [3] Boccaletto P, Machnicka MA, Purta E, et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res, 2018, 46(D1): D303-D307.
    [4] Roundtree IA, Evans ME, Pan T, et al. Dynamic RNA modifications in gene expression regulation. Cell, 2017, 169(7): 1187-1200.
    [5] Shi H, Wei J, He C. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell, 2019, 74(4): 640-650.
    [6] Zhong SL, Li HY, Bodi Z, et al. MTA is an Arabidopsis messenger RNA adenosine methylase and interacts with a homolog of a sex-specific splicing factor. Plant Cell, 2008, 20(5): 1278-1288.
    [7] Tan B, Liu H, Zhang S, et al. Viral and cellular N6-methyladenosine and N6, 2'-O-dimethyladenosine epitranscriptomes in the KSHV life cycle. Nat Microbiol, 2018, 3(1): 108-120.
    [8] Schwartz S, Agarwala SD, Mumbach MR, et al. High-resolution mapping reveals a conserved, widespread, dynamic mRNA methylation program in yeast meiosis. Cell, 2013, 155(6): 1409-1421.
    [9] Wang X, Zhao BS, Roundtree IA, et al. N6-methyladenosine modulates messenger RNA translation efficiency. Cell, 2015, 161(6): 1388-1399.
    [10] Li J, Xie H, Ying Y, et al. YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer, 2020, 19(1): 152.
    [11] Willyard C. An epigenetics gold rush: new controls for gene expression. Nature, 2017, 542(7642): 406-408.
    [12] Liu J, Harada BT, He C. Regulation of gene expression by N6-methyladenosine in cancer. Trends Cell Biol, 2019, 29(6): 487-499.
    [13] Zhao K, Yang CX, Li P, et al. Epigenetic role of N6-methyladenosine (m6A) RNA methylation in the cardiovascular system. J Zhejiang Univ Sci B, 2020, 21(7): 509-523.
    [14] Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol, 2011, 7(12): 885-887.
    [15] Jiao Y, Zhang J, Lu L, et al. The FTO gene regulates the proliferation and differentiation of pre-adipocytes in vitro. Nutrients, 2016, 8(2): 102.
    [16] Chen X, Zhou B, Luo Y, et al. Tissue distribution of porcine FTO and its effect on porcine intramuscular preadipocytes proliferation and differentiation. PLoS One, 2016, 11(3): e0151056.
    [17] Ben-Haim MS, Moshitch-Moshkovitz S, Rechavi G. FTO: linking m6A demethylation to adipogenesis. Cell Res, 2015, 25(1): 3-4.
    [18] Zhang M, Zhang Y, Ma J, et al. The demethylase activity of FTO (fat mass and obesity associated protein) is required for preadipocyte differentiation. PLoS One, 2015, 10(7): e0133788.
    [19] Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother, 2019, 112: 108613.
    [20] Merkestein M, Laber S, McMurray F, et al. FTO influences adipogenesis by regulating mitotic clonal expansion. Nat Commun, 2015, 6: 6792.
    [21] Wu RF, Liu YH, Yao YX, et al. FTO regulates adipogenesis by controlling cell cycle progression via m6A-YTHDF2 dependent mechanism. Biochim et Biophys Acta BBA-Mol Cell Biol Lipids, 2018, 1863(10): 1323-1330.
    [22] Hirayama M, Wei FY, Chujo T, et al. FTO demethylates cyclin D1 mRNA and controls cell-cycle progression. Cell Rep, 2020, 31(1): 107464.
    [23] Deng K, Zhang Z, Ren C, et al. FTO regulates myoblast proliferation by controlling CCND1 expression in an m6A-YTHDF2-dependent manner. Exp Cell Res, 2021, 401(2): 112524.
    [24] Shinohara S, Fujimori K. Promotion of lipogenesis by PPARγ-activated FXR expression in adipocytes. Biochem Biophys Res Commun, 2020, 527(1): 49-55.
    [25] Li KC, Chang YH, Yeh CL, et al. Healing of osteoporotic bone defects by baculovirus-engineered bone marrow-derived MSCs expressing MicroRNA sponges. Biomaterials, 2016, 74: 155-166.
    [26] Shen GS, Zhou HB, Zhang H, et al. The GDF11-FTO-PPARγ axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis. Biochim Biophys Acta BBA-Mol Basis Dis, 2018, 1864(12): 3644-3654.
    [27] Liu W, Zhou L, Zhou C, et al. GDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation. Nat Commun, 2016, 7: 12794.
    [28] Chen X, Hua W, Huang X, et al. Regulatory N6-methyladenosine methylation reveals the critical role of m6A in chicken adipose deposition. Front Cell Dev Biol, 2021, 9: 590468.
    [50] Sun L, Gao M, Qian Q, et al. Triclosan-induced abnormal expression of miR-30b regulates FTO-mediated m6A methylation level to cause lipid metabolism disorder in zebrafish. Sci Total Environ, 2021, 770: 145285.
    [51] Zhang XY, Evans TD, Je?ng SJ, ?t al. Clas?ical and alternative roles for autophagy in lipid metabolism[J]. Cu汲汲丠Op獩汮 L赩走id筯l,尠缲018, ??(3): ?吰3-11.?坢噲儯阾卛蠵輲橝张硂穡er卧卡儠孒戬 Zhang Y, Chen PH, et al. Targeted deletion of autophagy-related 5 (atg5) impairs adipogenesis in a cellular model and in mice. Autophagy, 2009, 5(8): 1118-1130.
    [53]?Zhang Y, Goldman S, Baerga R, et al. Adipose-specific deletion of autophagy-related gene 7 (atg7) in mice reveals a role in adipogenesis. PNAS, 2009, 106(47): 19860-19865.
    [54] Singh R, Xiang Y, Wang Y, et al. Autophagy regulates adipos? mass and differentiation in mice. J Clin Invest, 2009, 119(11): 3329-3339.
    [55] Wang XX, Wu RF, Liu YH, et al. m6A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7. Autophagy, 2020, 16(7): 1221-1235.
    [56] Song H, Wang Y,?Wang R, et al. SFPQ is an FTO-binding protein that facilitates the demethylation substrate preference. Cell Chem Biol, 2020, 27(3): 283-291. e6.
    [57] Wang L, Song C, Wang N, et al. NADP modulates RNA m6A methylation and adipogenesis via enhancing FTO activity. Nat Chem Biol, 202嬰嘬琠16弨昱2)刺嬠欱39笴-1402.
    [伵匸遝贠乓孯驮內舠灔匬甠杙剡癮硧稠轙尬 W卥孩縠轈, et al. Zfp217 mediates m6A mRNA methylation to orchestrate transcriptional and post-transcriptional regulation to promote adipogenic differentiation. Nucleic Acids Res, 2019, 47(12): 6130-6144.
    [59] Lan N, Lu Y, Zhang Y, et al. FTO-a common genetic basis for obesity and cancer. Front Genet, 2020, 11: 559138.
    [60] Liu Y, Liang GH, Xu HJ, et al. Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance. Cell Metab, 2021, 33(6): 1221-1233.
    [61] Feng ST, Qiu GQ, Yang LH, et al. Omeprazole impr?ves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation. Biosci Rep, 2021, 41(1): BSR20200842.
    [62] Huff S, T?wari SK, Gonzalez GM, et al. m6A-RNA demethylase FTO inhibitors impair self-renewal in glioblastoma stem cells. ACS Chem Biol, 2021, 16(2): 324-333.
    [63] Bai N, Gan Y, Li XT, et al. The role of chlorine atom on the binding between acrylonitrile derivatives and fat mass and obesity-associated protein. J Mol Recognit, 2021, 34(4): e2800.
    [64] Su R, Dong L, Li Y, et al. Targeting FTO suppresses cancer stem cell maintenance and immune evasion. Cancer Cell, 2020, 38(1): 79-96. e11.
    [65] Wang Y, Li J, Han X, et al. Identification of clausine E as an inhibitor of fat mass and obesity-associated protein (FTO) demethylase activity. J Mol Recognit, 2019, 32(10): e2800.
    [66] Peng SM, Xiao W, Ju DP, et al. Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1. Sci Transl Med, 2019, 11(488): eaau7116.
    [67] Van Der Werf I, Jamieson C. The Yin and Yang of RNA methylation: an imbalance of erasers enhances sensitivity to FTO demethylase small-molecule targeting in leukemia stem cells. Cancer Cell, 2019, 35(4): 540-541.
    [68] Li JY, Wang Y, Han XX, et al. The role of chlorine atom on the binding between 2-phenyl-1H-benzimidazole analogues and fat mass and obesity-associated protein. J Mol Recognit, 2019, 32(6): e2774.
    [69] Han X, Wang N, Li J, et al. Identification of nafamostat mesilate as an inhibitor of the fat mass and obesity-associated protein (FTO) demethylase activity. Chem Biol Interact, 2019, 297: 80-84.
    [70] Wang R, Han Z, Liu B, et al. Identification of natural compound radicicol as a potent FTO inhibitor. Mol Pharm, 2018, 15(9): 4092-4098.
    [71] Qiao Y, Yang Q, Song C, et al. Computational insights into the origin of decrease/increase in potency of N-CDPCB analogues toward FTO. J Biomol Struct Dyn, 2017, 35(8): 1758-1765.
    [72] Padariya M, Kalathiya U. Structure-based design and evaluation of novel N-phenyl-1H-indol-2-amine derivatives for fat mass and obesity-associated (FTO) protein inhibition. Comput Biol Chem, 2016, 64: 414-425.
    [73] McMurray F, Demetriades M, Aik W, et al. Pharmacological inhibition of FTO. PLoS One, 2015, 10(4): e0121829.
    [74] Huang Y, Yan J, Li Q, et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res, 2015, 43(1): 373-384.
    [75] Toh JDW, Sun L, Lau LZM, et al. A strategy based on nucleotide specificity leads to a subfamily-selective and cell-active inhibitor of N6-methyladenosine demethylase FTO. Chem Sci, 2015, 6(1): 112-122.
    [76] Chen BE, Ye F, Yu L, et al. Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor. J Am Chem Soc, 2012, 134(43): 17963-17971.
    [77] Zhang Y, Li QN, Zhou KY, et al. Identification of specific N6-methyladenosine RNA demethylase FTO inhibitors by single-quantum-dot-based FRET nanosensors. Anal Chem, 2020, 92(20): 13936-13944.
    [78] Thielen LA, Chen J, Jing G, et al. Identification of an anti-diabetic, orally available small molecule that regulates TXNIP expression and glucagon action. Cell Metab, 2020, 32(3): 353-365. e8.
    相似文献
    引证文献
    网友评论
    网友评论
    分享到微博
    发 布
引用本文

田婷婷,伊旭东,庞卫军. 脂肪含量和肥胖相关蛋白介导的mRNA m6A修饰对动物脂肪沉积的作用及其应用前景[J]. 生物工程学报, 2022, 38(1): 119-129

复制
分享
文章指标
  • 点击次数:337
  • 下载次数: 1366
  • HTML阅读次数: 1457
  • 引用次数: 0
历史
  • 收稿日期:2021-04-13
  • 在线发布日期: 2022-01-25
文章二维码
您是第6080919位访问者
生物工程学报 ® 2025 版权所有

通信地址：中国科学院微生物研究所    邮编：100101

电话：010-64807509   E-mail：cjb@im.ac.cn

技术支持：北京勤云科技发展有限公司