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    Fat mass and obesity-associated gene enhances oxidative stress and lipogenesis in nonalcoholic fatty liver disease. Guo Jianjin,Ren Wei,Li Aimei,Ding Ying,Guo Wanhua,Su Dongming,Hu Cheng,Xu Kuanfeng,Chen Heng,Xu Xinyu,Yang Tao,Jia Weiping Digestive diseases and sciences BACKGROUND AND AIM:Nonalcoholic fatty liver disease (NAFLD) is strongly associated with obesity, hyperlipidemia, and type 2 diabetes mellitus. Several studies have found that fat mass and the obesity-associated (FTO) gene is linked to obesity. The aim of this work is to investigate the expression and function of FTO in liver with lipid metabolism diseases. METHODS:We investigated the basal FTO expression in an NAFLD rat model and compared it with control subjects. The function of FTO in lipid metabolism was further studied in L02 cells through overexpression experiments. RESULTS:A significant increase in FTO mRNA and protein levels was found in the NAFLD group. In addition, the FTO levels were positively associated with malondialdehyde and superoxide dismutase concentrations. FTO overexpression in L02 cells enhanced lipogenesis and oxidative stress. CONCLUSIONS:This study demonstrates that increased FTO levels in the liver are involved in oxidative stress and lipid deposition, which characterize NAFLD. 10.1007/s10620-012-2516-6
    miR-149-3p Regulates the Switch between Adipogenic and Osteogenic Differentiation of BMSCs by Targeting FTO. Li Yuan,Yang Fan,Gao Manqi,Gong Rui,Jin Mengyu,Liu Tianyi,Sun Yi,Fu Yutuo,Huang Qi,Zhang Wenwen,Liu Shenzhen,Yu Meixi,Yan Gege,Feng Chao,He Mingyu,Zhang Lai,Ding Fengzhi,Ma Wenya,Bi Zhenggang,Xu Chaoqian,Yuan Ye,Cai Benzhi,Yang Lei Molecular therapy. Nucleic acids Bone marrow-derived mesenchymal stem cells (BMSCs) have been suggested to possess the capacity to differentiate into different cell lineages. Maintaining a balanced stem cell differentiation program is crucial to the bone microenvironment and bone development. MicroRNAs (miRNAs) have played a critical role in regulating the differentiation of BMSCs into particular lineage. However, the role of miR-149-3p in the adipogenic and osteogenic differentiation of BMSCs has not been extensively discovered. In this study, we aimed to detect the expression levels of miR-149-3p during the differentiation of BMSCs and investigate whether miR-149-3p participated in the lineage choice of BMSCs or not. Compared with mimic-negative control (NC), miR-149-3p mimic decreased the adipogenic differentiation potential of BMSCs and increased the osteogenic differentiation potential. Further analysis revealed that overexpression of miR-149-3p repressed the expression of fat mass and obesity-associated (FTO) gene through binding to the 3' UTR of the FTO mRNA. Also, the role of miR-149-3p mimic in inhibiting adipogenic lineage differentiation and potentiating osteogenic lineage differentiation was mainly through targeting FTO, which also played an important role in regulating body weight and fat mass. In addition, BMSCs treated with miR-149-3p anti-miRNA oligonucleotide (AMO) exhibited higher potential to differentiate into adipocytes and lower tendency to differentiate into osteoblasts compared with BMSCs transfected with NC. In summary, our results detected the effects of miR-149-3p in cell fate specification of BMSCs and revealed that miR-149-3p inhibited the adipogenic differentiation of BMSCs via a miR-149-3p/FTO regulatory axis. This study provided cellular and molecular insights into the observation that miR-149-3p was a prospective candidate gene for BMSC-based bone tissue engineering in treating osteoporosis. 10.1016/j.omtn.2019.06.023
    FTO: linking m6A demethylation to adipogenesis. Ben-Haim Moshe Shay,Moshitch-Moshkovitz Sharon,Rechavi Gideon Cell research Polymorphism of the FTO gene encoding an N(6)-methyladenosine (m(6)A) RNA demethylase was robustly associated with human obesity; however, the mechanism by which FTO affects metabolism, considering its emerging role in RNA modification, is still poorly understood. A new study published in Cell Research reports novel functions implicating FTO in the regulation of mRNA alternative splicing in the control of adipogenesis. 10.1038/cr.2014.162
    Regulation of FTO and FTM expression during human preadipocyte differentiation. Tews D,Fischer-Posovszky P,Wabitsch M Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme In genome-wide association studies (GWAS), polymorphisms in the first intron of FTO were shown to be associated with body fat mass. However, the functional properties of FTO and its nearby gene FTM are largely unknown. We examined the expression of these genes in subcutaneous adipose tissue and in isolated preadipocytes of lean and obese women. In in vitro differentiated primary human preadipocytes and in SGBS preadipocytes we found a decline in FTO and FTM expression during adipogenic differentiation. When investigating the hormonal regulation of FTO and FTM in adipocytes, insulin was identified as a key factor regulating FTM expression indicating a potential role of FTM in insulin regulated adipocyte metabolism. 10.1055/s-0030-1265130
    FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Zhao Xu,Yang Ying,Sun Bao-Fa,Shi Yue,Yang Xin,Xiao Wen,Hao Ya-Juan,Ping Xiao-Li,Chen Yu-Sheng,Wang Wen-Jia,Jin Kang-Xuan,Wang Xing,Huang Chun-Min,Fu Yu,Ge Xiao-Meng,Song Shu-Hui,Jeong Hyun Seok,Yanagisawa Hiroyuki,Niu Yamei,Jia Gui-Fang,Wu Wei,Tong Wei-Min,Okamoto Akimitsu,He Chuan,Rendtlew Danielsen Jannie M,Wang Xiu-Jie,Yang Yun-Gui Cell research The role of Fat Mass and Obesity-associated protein (FTO) and its substrate N6-methyladenosine (m6A) in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adipogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5'- and 3'-splice sites, spatially overlapping with mRNA splicing regulatory serine/arginine-rich (SR) protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenic regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis. 10.1038/cr.2014.151
    FTO influences adipogenesis by regulating mitotic clonal expansion. Merkestein Myrte,Laber Samantha,McMurray Fiona,Andrew Daniel,Sachse Gregor,Sanderson Jeremy,Li Mengdi,Usher Samuel,Sellayah Dyan,Ashcroft Frances M,Cox Roger D Nature communications The fat mass and obesity-associated (FTO) gene plays a pivotal role in regulating body weight and fat mass; however, the underlying mechanisms are poorly understood. Here we show that primary adipocytes and mouse embryonic fibroblasts (MEFs) derived from FTO overexpression (FTO-4) mice exhibit increased potential for adipogenic differentiation, while MEFs derived from FTO knockout (FTO-KO) mice show reduced adipogenesis. As predicted from these findings, fat pads from FTO-4 mice fed a high-fat diet show more numerous adipocytes. FTO influences adipogenesis by regulating events early in adipogenesis, during the process of mitotic clonal expansion. The effect of FTO on adipogenesis appears to be mediated via enhanced expression of the pro-adipogenic short isoform of RUNX1T1, which enhanced adipocyte proliferation, and is increased in FTO-4 MEFs and reduced in FTO-KO MEFs. Our findings provide novel mechanistic insight into how upregulation of FTO leads to obesity. 10.1038/ncomms7792
    FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. Claussnitzer Melina,Dankel Simon N,Kim Kyoung-Han,Quon Gerald,Meuleman Wouter,Haugen Christine,Glunk Viktoria,Sousa Isabel S,Beaudry Jacqueline L,Puviindran Vijitha,Abdennur Nezar A,Liu Jannel,Svensson Per-Arne,Hsu Yi-Hsiang,Drucker Daniel J,Mellgren Gunnar,Hui Chi-Chung,Hauner Hans,Kellis Manolis The New England journal of medicine BACKGROUND:Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. METHODS:We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR-Cas9 genome editing in samples from patients. RESULTS:Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR-Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. CONCLUSIONS:Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.). 10.1056/NEJMoa1502214
    FTO regulates adipogenesis by controlling cell cycle progression via mA-YTHDF2 dependent mechanism. Wu Ruifan,Liu Youhua,Yao Yongxi,Zhao Yuanling,Bi Zhen,Jiang Qin,Liu Qing,Cai Min,Wang Fengqin,Wang Yizhen,Wang Xinxia Biochimica et biophysica acta. Molecular and cell biology of lipids N-methyladenosine (mA) is the most prevalent internal mRNA modification in eukaryotes. Loss of mA demethylase FTO increases mA levels and inhibits adipogenesis of preadipocytes. However, its underlying mechanism remains elusive. Here, we demonstrated that silencing FTO inhibited adipogenesis of preadipocytes through impairing cell cycle progression at the early stage of adipogenesis. FTO knockdown markedly decreased the expression of CCNA2 and CDK2, crucial cell cycle regulators, leading to delayed entry of MDI-induced cells into G2 phase. Furthermore, the mA levels of CCNA2 and CDK2 mRNA were significantly upregulated following FTO knockdown. mA-binding protein YTHDF2 recognized and decayed methylated mRNAs of CCNA2 and CDK2, leading to decreased protein expression, thereby prolonging cell cycle progression and suppressing adipogenesis. Our work unravels that FTO regulates adipogenesis by controlling cell cycle progression in an mA-YTHDF2 dependent manner, which provides insights into critical roles of mA methylation in adipogenesis. 10.1016/j.bbalip.2018.08.008
    FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications. Martin Carli Jayne F,LeDuc Charles A,Zhang Yiying,Stratigopoulos George,Leibel Rudolph L Journal of lipid research SNPs in the first intron of α-ketoglutarate-dependent dioxygenase () convey effects on adiposity by mechanisms that remain unclear, but appear to include modulation of expression of itself, as well as other genes in expression is lower in fibroblasts and iPSC-derived neurons of individuals segregating for obesity risk alleles. We employed in vitro adipogenesis models to investigate the molecular mechanisms by which Fto affects adipocyte development and function. expression was upregulated during adipogenesis, and was required for the maintenance of and / expression in murine and human adipocytes in vitro. knockdown decreased the number of 3T3-L1 cells that differentiated into adipocytes as well as the amount of lipid per mature adipocyte. This effect on adipocyte programming was conveyed, in part, by modulation of CCAAT enhancer binding protein (C/ebp)β-regulated transcription. We found that Fto also affected transcription by demethylating DNA N6-methyldeoxyadenosine in the promoter. Fto is permissive for adipogenesis and promotes maintenance of lipid content in mature adipocytes by enabling C/ebpβ-driven transcription and expression of These findings are consistent with the loss of fat mass in mice segregating for a dominant-negative allele. 10.1194/jlr.M085555
    FTO knockout in adipose tissue effectively alleviates hepatic steatosis partially via increasing the secretion of adipocyte-derived IL-6. Zeng Botao,Wu Ruifan,Chen Yushi,Chen Wei,Liu Youhua,Liao Xing,Guo Guanqun,Wang Xinxia Gene OBJECTIVE:Adipose dysfunction affects the secretion of adipokines and mediates the hepatic physiological changes. Fat mass and obesity associated protein (FTO) plays a crucial part in fat deposition but the crosstalk between FTO-mediated secretion of adipokines and hepatic steatosis is not clear. METHODS:Firstly, adipose-selective FTO knockout (FTO) and control (FTO) mice were induced by high fat diet (HFD). Then qRT-PCR assay was performed to analyze the expressions of hepatic lipid metabolism genes and adipocytokines gene of inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT). Afterwards, 3T3-L1 cells were knocked out IL-6 and co-cultured with AML12 cells (3T3-L1 siIL-6/AML12) and the expressions of hepatic lipid lipolysis genes were measured. Finally, we detected the hepatic lipid metabolism genes expressions in AML12 cells with the medium from 3T3-L1 cells or IL-6 treatment. RESULTS:FTO effectively alleviated HFD-induced hepatic steatosis in mice and improved the transcription level of genes involved in hepatic lipolysis. Further investigation demonstrated that FTO knockout increased level of IL-6 in adipose tissues and 3T3-L1 cells. Compared to 3T3-L1/AML12, our results showed lipolysis-related genes expressions were dramatically inhibited in 3T3-L1 siIL-6/AML12. Finally, both depletion of FTO in adipocytes and IL-6 supplement led to increased lipolysis genes expressions in AML12 cells. CONCLUSIONS:FTO knockout in adipose tissue alleviated hepatic steatosis via targeting adipocyte-derived IL-6. 10.1016/j.gene.2022.146224
    FTO reduces mitochondria and promotes hepatic fat accumulation through RNA demethylation. Kang Huifang,Zhang Zhiwang,Yu Lin,Li Yixing,Liang Mingzhen,Zhou Lei Journal of cellular biochemistry Fat mass and obesity-associated protein (FTO) is a RNA demethylase, whether FTO regulates fat metabolism through its demethylation is unclear. The results of this study confirmed that N6-methyladenosine (m A) is associated with fat accumulation both in vivo and in vitro. The data showed that FTO down-regulated m A levels, decreased mitochondrial content, and increased triglyceride (TG) deposition. However, an FTO (R316A) mutant lacking demethylation activity could not regulate mitochondria and TG content, indicating that FTO affects mitochondrial content and fat metabolism by modulating m A levels in hepatocytes. In addition, the regulatory roles of cycloleucine (methylation inhibitor) and betaine (methyl donor) could regulate m A levels and fat deposition. This work clarified that the demethylation function of FTO plays an essential role in the fat metabolism of hepatocytes and links the epigenetic modification of RNA with fat deposition, thereby providing a new target (m A) for regulation of hepatic fat metabolism. 10.1002/jcb.26746