Metformin combats obesity by targeting FTO in an m⁶A-YTHDF2-dependent manner

References

• Seravalle G, Grassi G. Obesity and hypertension. Pharmacol Res. 2017;122:1–7.
   PubMed Web of Science ®Google Scholar
• Hsia DS, Heymsfield SB. Reducing diabetes risk at an early age. Nat Med. 2018;24(6):708–710.
   PubMed Web of Science ®Google Scholar
• Verbovoy AF, Pashentseva AV, Sharonova LA. [Obesity and cardiovascular system]. Klin Med (Mosk). 2017;95(1):31–35.
   PubMedGoogle Scholar
• Taubes G. Cancer research. Unraveling the obesity-cancer connection. Science. 2012;335(6064):28, 30–2.
   PubMed Web of Science ®Google Scholar
• Bailey CJ, Day C. Metformin: its botanical background. Pract Diab Int. 2004;21(3):115–117.
   Google Scholar
• Yerevanian A, Soukas AA. Metformin: mechanisms in human obesity and weight loss. Curr Obes Rep. 2019;8(2):156–164.
   PubMed Web of Science ®Google Scholar
• Lentferink YE, Knibbe C, van der Vorst M. Efficacy of metformin treatment with respect to weight reduction in children and adults with obesity: a systematic review. Drugs. 2018;78(18):1887–1901.
   PubMed Web of Science ®Google Scholar
• Syngelaki A, Nicolaides KH, Balani J, et al. Metformin versus placebo in obese pregnant women without diabetes mellitus. N Engl J Med. 2016;374(5):434–443.
   PubMed Web of Science ®Google Scholar
• Coll AP, Chen M, Taskar P, et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature. 2020;578(7795):444–448.
   PubMed Web of Science ®Google Scholar
• Jing Y, Wu F, Li D, et al. Metformin improves obesity-associated inflammation by altering macrophages polarization. Mol Cell Endocrinol. 2018;461:256–264.
   PubMed Web of Science ®Google Scholar
• Chen D, et al. Dual effects of metformin on adipogenic differentiation of 3T3-L1 preadipocyte in AMPK-dependent and independent manners. Int J Mol Sci. 2018;19(6):1547.
   Web of Science ®Google Scholar
• Wang H, Liu S-H, Zhai Y-M, et al. [Metformin influences the effect of adipocytes on leukemia cell chemoresistance through regulation of adipogenesis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015;23(2):340–344.
   PubMedGoogle Scholar
• Kim B-H, Han S, Lee H, et al. Metformin enhances the anti-adipogenic effects of atorvastatin via modulation of STAT3 and TGF-β/Smad3 signaling. Biochem Biophys Res Commun. 2015;456(1):173–178.
   PubMedGoogle Scholar
• Zhao X, Yang Y, Sun B-F, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Res. 2014;24(12):1403–1419.
   PubMed Web of Science ®Google Scholar
• Wu R, Liu Y, Yao Y, et al. FTO regulates adipogenesis by controlling cell cycle progression via m6A-YTHDF2 dependent mechanism. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863(10):1323–1330.
   PubMed Web of Science ®Google Scholar
• Merkestein M, Laber S, McMurray F, et al. FTO influences adipogenesis by regulating mitotic clonal expansion. Nat Commun. 2015;6:6792.
   PubMed Web of Science ®Google Scholar
• Wu R, Yao Y, Jiang Q, et al. Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m6A-YTHDF2-dependent manner. Int J Obes (Lond). 2018;42(7):1378–1388.
   PubMed Web of Science ®Google Scholar
• Yao Y, Bi Z, Wu R, et al. METTL3 inhibits BMSC adipogenic differentiation by targeting the JAK1/STAT5/C/EBPβ pathway via an m6A-YTHDF2-dependent manner. Faseb J. 2019;33(6):7529–7544.
   PubMed Web of Science ®Google Scholar
• Wu R, Guo G, Bi Z, et al. m6A methylation modulates adipogenesis through JAK2-STAT3-C/EBPβ signaling. Biochim Biophys Acta Gene Regul Mech. 2019;1862(8):796–806.
   PubMed Web of Science ®Google Scholar
• Wang X, Wu R, Liu Y, et al. m6A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7 . Autophagy. 2020;16(7):1221–1235.
   PubMed Web of Science ®Google Scholar
• Cheng L, Zhang X, Huang Y-Z, et al. Metformin exhibits antiproliferation activity in breast cancer via miR-483-3p/METTL3/m6A/p21 pathway. Oncogenesis. 2021;10(1):7.
   PubMed Web of Science ®Google Scholar
• Wu D, Hu D, Chen H, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature. 2018;559(7715):637–641.
   PubMed Web of Science ®Google Scholar
• Zong X, Xiao X, Shen B, et al. The N6-methyladenosine RNA-binding protein YTHDF1 modulates the translation of TRAF6 to mediate the intestinal immune response. Nucleic Acids Res. 2021;49(10):5537–5552.
   PubMed Web of Science ®Google Scholar
• Dominissini D, Moshitch-Moshkovitz S, Schwartz S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485(7397):201–206.
   PubMed Web of Science ®Google Scholar
• Wang X, Lu Z, Gomez A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505(7481):117–120.
   PubMed Web of Science ®Google Scholar
• Carreras-Badosa G, et al. A 24-month metformin treatment study of children with obesity: changes in circulating GDF-15 and associations with changes in body weight and visceral fat. Pediatr Obes. 2021;17(2):e12845.
   PubMed Web of Science ®Google Scholar
• Ning H-H, Le J, Wang Q, et al. The effects of metformin on simple obesity: a meta-analysis. Endocrine. 2018;62(3):528–534.
   PubMed Web of Science ®Google Scholar
• Maniar K, Moideen A, Bhattacharyya R, et al. Metformin exerts anti-obesity effect via gut microbiome modulation in prediabetics: a hypothesis. Med Hypotheses. 2017;104:117–120.
   PubMed Web of Science ®Google Scholar
• Zhang X, Zhao Y, Xu J, et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015;5:14405.
   PubMed Web of Science ®Google Scholar
• Kim AJ, Chang JY-A, Shi L, et al. The effects of metformin on Obesity-Induced dysfunctional retinas. Invest Ophthalmol Vis Sci. 2017;58(1):106–118.
   PubMed Web of Science ®Google Scholar
• Kim EK, Lee SH, Jhun JY, et al. Metformin prevents fatty liver and improves balance of white/brown adipose in an obesity mouse model by inducing FGF21. Mediators Inflamm. 2016;2016:1–13.
   Web of Science ®Google Scholar
• Gregoire FM, Smas CM, Sul HS. Understanding adipocyte differentiation. Physiol Rev. 1998;78(3):783–809.
   PubMed Web of Science ®Google Scholar
• Harashima H, Dissmeyer N, Schnittger A. Cell cycle control across the eukaryotic kingdom. Trends Cell Biol. 2013;23(7):345–356.
   PubMed Web of Science ®Google Scholar
• Bertoli C, Skotheim JM, de Bruin RA. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol. 2013;14(8):518–528.
   PubMed Web of Science ®Google Scholar
• Yang Q, Liang X, Sun X, et al. AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab. 2016;24(4):542–554.
   PubMed Web of Science ®Google Scholar
• Huang R, Wang Y, Ge H, et al. Restoration of TET2 deficiency inhibits tumor growth in head neck squamous cell carcinoma. Ann Transl Med. 2020;8(6):329.
   PubMed Web of Science ®Google Scholar
• Wu R, Wang X. Epigenetic regulation of adipose tissue expansion and adipogenesis by N(6)-methyladenosine. Obes Rev. 2021;22(2):e13124.
   PubMed Web of Science ®Google Scholar
• DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The multicenter metformin study group. N Engl J Med. 1995;333(9):541–549.
   PubMed Web of Science ®Google Scholar
• Feng W-H, Bi Y, Li P, et al. Effects of liraglutide, metformin and gliclazide on body composition in patients with both type 2 diabetes and non-alcoholic fatty liver disease: a randomized trial. J Diabetes Investig. 2019;10(2):399–407.
   PubMed Web of Science ®Google Scholar
• Glueck CJ, Fontaine RN, Wang P, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;50(7):856–861.
   PubMed Web of Science ®Google Scholar
• Paolisso G, et al. Effect of metformin on food intake in obese subjects. Eur J Clin Invest. 1998;28(6):441–446.
   PubMed Web of Science ®Google Scholar
• Tang QQ, Lane MD. Adipogenesis: from stem cell to adipocyte. Annu Rev Biochem. 2012;81:715–736.
   PubMed Web of Science ®Google Scholar
• Wang Y, Xu W, Yan Z, et al. Metformin induces autophagy and G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer Res. 2018;37(1):63.
   PubMed Web of Science ®Google Scholar
• Li B, Zhou P, Xu K, et al. Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int J Biol Sci. 2020;16(1):74–84.
   PubMed Web of Science ®Google Scholar
• Du H, Zhao Y, He J, et al. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 2016;7:12626.
   PubMed Web of Science ®Google Scholar