Changes of plasma METTL3, WTAP and FTO levels in patients with systemic lupus erythematosus and their correlation with clinical indicators / 中国医师杂志

Objective:To explore the clinical significance of N6-methyladenine (m6A) in systemic lupus erythematosus (SLE) by comparing the changes in plasma levels of m6A modification related proteins [methyltransferase 3 (METTL3), methyltransferase 14 (METTL14), Wilms tumor 1 associated protein (WTAP), AlkB homologous protein 5 (ALKBH5), and fat mass and obesity-associated protein (FTO)] and m6A between patients with systemic lupus erythematosus (SLE) and healthy controls.Methods:A total of 64 SLE patients admitted to the Seventh Affiliated Hospital of Sun Yat-Sen University from May 2020 to June 2022 and 24 healthy volunteers during the same period were selected to compare and analyze the plasma levels of METTL3, METTL14, WTAP, ALKBH5, FTO and m6A between the two groups. The correlation between METTL3, WTAP, FTO levels and clinical indicators was analyzed.Results:The plasma METTL3 level of SLE patients was significantly higher than that of control group ( P<0.05), and the plasma WTAP and FTO levels were significantly lower than those of control group (all P<0.05). In SLE patients, plasma METTL3 level was negatively correlated with hemoglobin level ( r=-0.344, P<0.05), plasma FTO level was positively correlated with plasma IgM level ( r=0.337, P<0.05), and plasma IgA level was negatively correlated with SLE patients ( r=-0.286, P<0.05). The incidence of renal involvement and positive rate of plasma anti-histone antibody were higher in SLE patients with high METTL3 level (all P<0.05). The positive rates of plasma anti-dsDNA antibody, anti-SM antibody and AuaA antibody were higher in SLE patients with low FTO level (all P<0.05). Conclusions:The plasma METTL3 level in SLE patients are significantly increased, while the plasma WTAP and FTO levels are significantly reduced, which are related to various clinical indicators and may be related to the onset of SLE.

Effects of chronic restraint stress on the expression of N6-methyladenosine and related enzymes in the hippocampus of mice / 解剖学报

Objective To investigate the effect of chronic restraint stress on the expression of N6-methyladenosine (m6A)and related enzymes in the hippocampus of mice. Methods Twenty C57BL/6J male mice were randomly divided into control group and chronic restraint stress (CRS) group, the model group was given for 3 weeks chronic restraint stress to establish a mouse anxiety model. Open field test and elevated plus maze test were used to detect anxiety-like behavior; Immunohistochemistry and m6A RNA methylation assay were used to detect the expression changes of mouse hippocampal m6A; Western blotting and Real-time PCR were used to analyze hippocampal m6A related enzymes expression. Results 1.The behavioral results showed that, compared with the control group, the CRS group showed significantly reduced time spent in the center of the open field(P<0.01), the CRS group showed significantly reduced exploration time in the open arm of elevated plus maze (P<0.0001); 2. Immunohistochemical results showed that, compared with the control group, the hippocampal m6A content in the CRS group reduced significantly (P < 0.001); The results of the m6A RNA methylation assay showed that, compared with the control group, the CRS group showed significantly reduced amount of hippocampal m6A(P<0.05); 3. Real-time PCR results showed that the expression of hippocampal demethylase anaplastic lymphoma kinase B(AlkB) homolog 5(ALKBH5) (P<0.001) and fat mass and obestity associated protein(FTO) (P< 0.05) in the CRS group significantly up-regulated, the expression of methylase Wilms' tumour 1-associating protein (WTAP) (P<0.05) was significantly down-regulated compared with the control group; The expression of m6A methylation binding protein YTH domaincontaining family protein 3 (YTHDF3) (P < 0.05) and YTH domaincontaining protein 2 (YTHDC2) (P < 0.01) was significantly up-regulated. Western blotting result showed that, compared with the control group, the mouse hippocampal demethylase ALKBH5 (P < 0.05) and FTO (P < 0.05) expression in the CRS group significantly up-regulated, the expression of WTAP (P<0.01) was significantly down-regulated; m6A methylation binding protein YTHDF3 (P<0.01) and YTHDC2 (P<0.05) were significantly up-regulated. Conclusion In the anxiety model induced by chronic restraint stress, the expression of m6A in the hippocampus of mice is down-regulated. The mechanism may be related to the up-regulation of the m6A demethylase ALKBH5 and FTO or the down-regulation of the methylase WTAP.

The role of the fat mass and obesity-associated protein in ischemia-reperfusion injury of human renal tubular epithelial cells / 中华实用儿科临床杂志

Objective:To explore the role of the fat mass and obesity-associated protein (FTO) in human renal tubular epithelial cells (HK-2) suffering ischemia-reperfusion injury (IRI).Methods:The in vitro IRI mo-del was established in HK-2 cells by induction with antimycin A, A23187 and 2-deoxy-D-glucose.The cells were divided into control group and ischemia-reperfusion group (I/R group). The mRNA and protein expressions of FTO, B-cell lymphoma / leukemia 2(Bcl-2)-associated X(Bax), Bcl-2 and cleaved cysteinyl aspartate specific proteinase(cleaved Caspase-3) in HK-2 cells before and after IRI were detected by real-time fluorescent quantitative PCR(qPCR) and Western blot, respectively.Cell apoptosis was measured using flow cytometry.The level ofe N 6-methy-ladenosine (m 6A) RNA was detected by colorimetry. Results:(1) The mRNA expressions of FTO (0.15±0.05 vs.1.00±0.23) and Bcl-2 (0.14±0.07 vs.1.02±0.25) in I/R group were significantly lower than those in control group; While those of Bax (3.10±0.35 vs.1.00±0.13) and cleaved Caspase-3 (4.21±0.56 vs.1.00±0.09) were significantly higher ( t=6.28, 5.84, -9.83, and -9.84, respectively, all P<0.01). (2) The protein expressions of FTO (0.69±0.14 vs.1.37±0.02) and Bcl-2 (0.50±0.12 vs.1.25±0.21) were significantly lower in I/R group than those of control group; While those of Bax (1.04±0.08 vs.0.57±0.06) and cleaved Caspase-3 (0.99±0.05 vs.0.36±0.07) were significantly higher ( t=8.10, 5.49, -8.22, and -12.09, respectively, all P<0.05). (3) Compared with the control group, the apoptosis rate of HK-2 cells in I/R group was significantly higher [(61.70±1.01)% vs.(0.16±0.10)%, t=63.80, P<0.01]. (4) Compared with the control group, the percentage of m 6A modification level in total RNA in I/R group was significantly higher [(3.13±0.21)% vs.(1.10±0.26)%, t=-10.61, P<0.01]. Conclusions:FTO-mediated RNA m 6A modification may affect renal IRI by regulating the apoptosis of HK-2 cells.

Effects of aluminum on expressions of fat mass and obesity-associated protein and brain-derived neurotrophic factor in rat brain and PC12 cells / 环境与职业医学

Background Chemical modification of RNA is a recent hotspot in the field of epigenetics, but the specific mechanism of chemical modification of RNA in aluminum neurotoxicity has not been fully reported. Objective To investigate the alterations of fat mass and obesity-associated protein (FTO), that demethylates N6-methyladenosine (m6A), and brain-derived neurotrophic factor (BDNF) in different brain regions of rats and rat adrenal pheochromocytoma differentiated cells (PC12 cells) following aluminum exposure. Methods Animal experiment: Twenty-four healthy male SD rats were randomly divided into a control group (normal saline) and 10, 20, and 40 μmol·kg−1 exposure groups according to body weight, with 6 rats in each group. Maltol aluminum [Al(mal)3] was injected intraperitoneally every other day for 3 months. Cell experiment: PC12 cells were divided into a control group and 100, 200, and 400 μmol·L−1 exposure groups exposed to Al(mal)3 for 24 h. After exposure, the learning and memory ability of rats was measured by water maze experiment, and the protein expression levels of FTO and BDNF in rat cortex (n=6) and hippocampus (n=6) samples as well as in PC12 cells (n=5) were determined by Western blotting. Results The results of water maze test showed that the escape latency of the 40 μmol·kg−1Al(mal)3 group was higher than those of the control group, the 10 μmol·kg−1Al(mal)3 group, and the 20 μmol·kg−1Al(mal)3 group on day 3, 4, and 5 of training (P<0.05). The retention time of the target quadrant of the 40 μmol·kg−1Al(mal)3 group was also reduced compared with that of the control group (P<0.05), indicating that aluminum exposure damaged the learning and memory ability of the rats. The Western blotting results showed that in the cortex, compared with the control group, the protein expression levels of FTO and BDNF in the aluminum treated groups were decreased (P<0.05). In the hippocampus, compared with the control group, the protein expression levels of FTO and BDNF in the 20 μmol·kg−1 and the 40 μmol·kg−1Al(mal)3 groups were decreased (P<0.05). In PC12 cells, compared with the control group, the protein expression levels of FTO and BDNF in the aluminum treated groups were decreased (P<0.05). Conclusion Aluminum-induced learning and memory impairment is related to a simultaneous reduction of FTO and BDNF protein expressions, suggesting that m6A methylation may be involved.

Research progress of N6-methyladenine demethylase inhibitors / 中国药科大学学报

@#N6-methyladenine (m6A) modification, the most abundant and dynamic chemical modification on messenger RNA, plays an essential role in physiological and pathological progress.Recent studies have found that tumor progression can be affected by altering the m6A modification level of target genes. Therefore, small molecule targeted m6A demethylase can be used as a new anti-tumor strategy.This review focuses on the regulatory mechanism of m6A demethylases, including fat mass and obesity-associated protein (FTO) and AlkB homlog 5 (ALKBH5), as well as their biological functions in tumors, and summarizes the research progress of their small molecule inhibitors.

Exploration and prospects of fat mass and obesity-associated in glioblastoma / 国际外科学杂志

Glioblastoma (GBM) is a common malignant neuroepithelial tumor of the central nervous system with rapid progression and high drug resistance. Fat mass and obesity associated (FTO), as the main demethylase in the modification process of N6-methyladenosine, is widely involved in GBM regulation, including tumor occurrence and development. It is also associated with the mutation of isocitrate dehydrogenase. The role of FTO in the aspects of biological function, glioblastoma stem cell sustaining and selfrenewing and chemotherapy resistance remained contentious. In this paper, FTO is preliminarily described through bioinformatics and current research, and the future research is prospected from the perspectives of energy metabolism, small molecule RNA regulation and post-translational modification.

FTO improves myocardial fibrosis by reducing m6A modification of DKK2 and promoting DKK2 expression / 西安交通大学学报(医学版)

【Objective】 To explore the relationship of fat mass and obesity-associated protein (FTO) with the m6A modification and expression level of DKK2 in the process of myocardial fibrosis. 【Methods】 Cardiac fibroblasts (CFs) were grouped as follows: Control group, AngⅡ-treated group, AngⅡ+EV group (transfected with empty vector and negative control siRNA and then treated with AngⅡ), AngⅡ+FTO-O group (transfected with FTO overexpression vector and then treated with AngⅡ), and AngⅡ+FTO-O+DKK2 siRNA group (treated with AngⅡ after co-transfection of FTO overexpression vector and DKK2 siRNA). Mice were divided into the following groups: Control group (sham operation group), AMI group (constructing acute myocardial infarction model), AMI+EV group (AMI mice were intraperitoneally injected with nanoparticles containing empty vector), and AMI+FTO-O group (AMI mice were intraperitoneally injected with nanoparticles containing FTO overexpression vector). Then, the expressions of FTO and DKK2 were detected by fluorescence quantitative PCR and Western blotting, the m6A modification level of DKK2 was detected by RNA binding protein immunoprecipitation, the cell viability was detected by CCK-8, the cardiac function of AMI mice was evaluated, and the cardiac pathological changes of mice were detected by HE and Masson staining. 【Results】 AngⅡ inhibited the expression of FTO, thereby enhancing the m6A modification level of DKK2 and downregulating the expression of DKK2 (P<0.05). AngⅡ promoted cell viability and enhanced the expressions of α-SMA, collagen Ⅰ and collagen Ⅲ (P<0.05). FTO overexpression significantly blocked the above-mentioned regulatory effects of AngⅡ (P<0.05), but DKK2 siRNA could antagonize the effect of FTO overexpression on AngⅡ. The expressions of FTO and DKK2 were downregulated in AMI mice, and the m6A modification level of DKK2 was increased (P<0.05). When FTO was overexpressed, the expressions of FTO and DKK2 in AMI mice were significantly restored, the m6A modification level of DKK2 and myocardial fibrosis were significantly reduced (P<0.05), and the cardiac pathological changes were significantly improved. 【Conclusion】 FTO can promote the expression of DKK2 by reducing the m6A modification level of DKK2, thereby inhibiting the progression of myocardial fibrosis. This indicates that FTO/DKK2 pathway is a key pathway in regulating myocardial fibrosis.

Changes of mRNA N6-methyladenosine methylation in blood of patients with Alzheimer's disease / 中华行为医学与脑科学杂志

Objective:To explore the changes of mRNA N6-methyladenosine methylation level and methyltransferase-like 3 (METTL3) and demethylase fat mass and obesity-associated (FTO) in the blood of patients with Alzheimer's disease (AD) compared with normal controls.Methods:From January 2020 to June 2021, totally 40 AD patients treated in the outpatient and inpatient department of Neurology of the Affiliated Hospital of Jining Medical University were selected as the patient group, and 40 healthy volunteers as the control group. The blood samples were collected to extract plasma and peripheral blood mononuclear cells for enzyme-linked immunosorbent assay (ELISA), Western blot (WB), quantitative real-time PCR (qPCR) and m6A methylation quantification experiments respectively to detect the methylation levels of METTL3, FTO and m6A. The data were analyzed by SPSS 23.0 statistical software for t-test. Results:The plasma concentrations of METTL3 and FTO protein in AD group were lower than those in control group (METTL3: (22.33±3.01)ng/mL, (25.63±1.70)ng/mL, t=6.055, P<0.01; FTO: (63.51±4.95)pg/mL, (69.60±4.60)pg/mL, ( t=5.704, P<0.01). The band gray values of METTL3 and FTO protein in blood cells in AD group were lower than those in control group (METTL3: 0.399 5±0.028 7, 0.676 6±0.053 3, t=7.935, P=0.001; FTO: 0.439 4±0.017 8, 0.782 6±0.087 6, t=6.652, P=0.003). The expression levels of METTL3 and FTO in blood cell RNA in AD group were lower than those in control group (METTL3: 0.387 8±0.020 3, 1.010 0±0.177 0, t=6.041, P=0.004; FTO: 0.442 8±0.037 1, 1.003 0±0.090 4, t=9.931, P=0.001). The levels of m6A in blood cell RNA in AD group were lower than those in control group((0.000 571±0.000 167)%, (0.002 514±0.001 284)%, t=6.041, P=0.004). Conclusion:The levels of METL3, FTO and m6A methylation are down-regulated in the plasma and peripheral blood mononuclear cells of patients with AD, indicating that there is a certain association between mRNA N6-methyladenosine methylation and AD.

The effect of fat mass and obesity associated proteins mediated mRNA m6A modification on animal fat deposition and its application prospects / 生物工程学报

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.

Fto polymorphism and physical fitness in obese schoolchildren after an intervention program / Polimorfismo no gene fto e aptidão física em escolares obesos após programa de intervenção / Polimorfismo en el gene fto y aptitud física en escolares obesos después de programa de intervención

ABSTRACT Introduction: Recent studies have shown that the association of FTO rs9939609 gene polymorphism with obesity depends on the level of the individual's physical activity. However, there are some studies that evaluated physical fitness, health, and motor performance in relation to the rs9939609 FTO gene polymorphism. Objective: To evaluate how the rs9939609 FTO gene polymorphism affects the results of physical fitness tests related to health and athletic performance in schoolchildren after 4 months of intervention of physical exercise. Method: The rs9939609 FTO gene polymorphism was genotyped in a total of 36 schoolchildren from southern Brazil, aged 8 to 16 years. Body mass index (BMI), health-related physical fitness (cardiorespiratory fitness, abdominal strength/endurance, and flexibility) and motor performance (upper and lower limb strength, agility, and speed) were evaluated. The intervention included exercise strategies based on Physical Education, healthy eating, and oral and postural care. Results: In the experimental group, after the intervention, significant differences were noted in individuals with the TT genotype. These individuals showed improvements in abdominal strength (p=0.025), lower limb strength (p=0.037) and agility (p=0.021). For individuals with the AA/AT genotype, improvements in flexibility (p=0.026), abdominal strength (p=0.002), upper limb strength (p=0.008) and lower limb strength (p=0.001) were observed. However, these differences were not statistically significant when comparing the TT and AT/AA genotypes. Conclusions: The experimental group showed improvements in abdominal strength, lower limb strength, and speed. Yet, individuals with different genotypes (AA/AT and TT) for polymorphism rs9939609 exhibited similar values for indicators of physical fitness, health, and motor performance. Level of Evidence II; Lesser quality RCT.

RESUMO Introdução: Estudos recentes demonstraram que a associação do polimorfismo do gene FTO rs9939609 e a obesidade dependem do nível de atividade física de um indivíduo. No entanto, existem alguns estudos que avaliaram a aptidão física, a saúde e o desempenho motor com relação ao polimorfismo rs9939609 do gene FTO. Objetivo: Avaliar como o polimorfismo rs9939609 do gene FTO afeta os resultados dos testes de aptidão física relacionados com a saúde e o desempenho atlético em escolares após 4 meses de intervenção com exercícios físicos. Método: O polimorfismo rs9939609 do gene FTO foi genotipado em um total de 36 escolares do sul do Brasil, com idades entre 8 e 16 anos. O índice de massa corporal (IMC), a aptidão física relacionada com a saúde (aptidão cardiorrespiratória, força abdominal/resistência e flexibilidade) e desempenho motor (força de membros superiores e inferiores, agilidade e velocidade) foram avaliados. A intervenção teve como base estratégias de exercícios da Educação Física e alimentação saudável, além de cuidados bucais e posturais. Resultados: No grupo experimental, após a intervenção, observaram-se diferenças significativas em indivíduos com o genótipo TT. Esses indivíduos apresentaram melhorias na força abdominal (p = 0,025), força dos membros inferiores (p = 0,037) e agilidade (p = 0,021). Para os indivíduos com o genótipo AA/AT, foram observadas melhorias na flexibilidade (p = 0,026), força abdominal (p = 0,002), força dos membros superiores (p = 0,008) e força dos membros inferiores (p = 0,001). No entanto, essas diferenças não foram estatisticamente significantes ao se comparar os genótipos TT e AT/AA. Conclusões: O grupo experimental apresentou melhorias na força abdominal, força dos membros inferiores e velocidade. Contudo, indivíduos com diferentes genótipos (AA/AT e TT) para o polimorfismo rs9939609 exibiram valores semelhantes para indicadores de aptidão física, saúde e desempenho motor. Nível de Evidência II, ECRC de menor qualidade.

RESUMEN Introducción: Estudios recientes han demostrado que la asociación del polimorfismo del gen FTO rs9939609 y la obesidad dependen del nivel de actividad física de um individuo. Sin embargo, existen algunos estudios que evaluaron la aptitud física, la salud y el rendimiento motor con relación al polimorfismo rs9939609 del gen FTO. Objetivo: Evaluar cómo el polimorfismo rs9939609 del gen FTO afecta los resultados de las pruebas de aptitud física relacionadas con la salud y el desempeño atlético en escolares después de 4 meses de intervención con ejercicios físicos. Método: El polimorfismo rs9939609 del gen FTO fue genotipado en un total de 36 escolares del sur de Brasil, con edades entre 8 y 16 años. El índice de masa corporal (IMC), la aptitud física relacionada con la salud (aptitud cardiorrespiratoria, fuerza abdominal/resistencia y flexibilidad) y rendimiento motor (fuerza de las extremidades superiores e inferiores, agilidad y velocidad) fueron evaluados. La intervención tuvo como base estrategias de ejercicios de Educación Física y alimentación saludable, además de cuidados bucales y posturales. Resultados: En el grupo experimental, después de la intervención, se observaron diferencias significativas en individuos con el genotipo TT. Estos individuos presentaron mejoras en la fuerza abdominal (p = 0,025), fuerza de las extremidades inferiores (p = 0,037) y agilidad (p = 0,021). Para las personas con el genotipo AA/AT, se observaron mejoras en la flexibilidad (p = 0,026), fuerza abdominal (p = 0,002), fuerza de las extremidades superiores (p = 0,008) y fuerza de las extremidades inferiores (p = 0,001). Sin embargo, estas diferencias no fueron estadísticamente significativas al comparar los genotipos TT y AT/AA. Conclusiones: El grupo experimental presentó mejoras en la fuerza abdominal, fuerza de las extremidades inferiores y velocidad. No obstante, individuos con diferentes genotipos (AA/AT y TT) para el polimorfismo rs9939609 mostraron valores similares para indicadores de aptitud física, salud y rendimiento motor. Nivel de Evidencia II; ECRC de menor calidad.

Correlation Study on FTO Expression and Insulin Secretion Level in Pregnant Women / 现代检验医学杂志

Objective To evaluate the correlation of maternal FTO expression and insulin secretion levels in pregnant women.Methods In outpatient of Zhuhai Municipal Maternal and Child Healthcare Hospital,60 cases of pregnant women with gestational diabetes mellitus (GDM) and 60 cases of healthy pregnant women were recruited in this study from March 2016 to August 2016.Each pregnant woman was taken two tubes of venous blood.Lymphocytes was isolated from one tube of anticoagulated whole blood.The expression of FTO mRNA in lymphocytes was investigated using RT-PCR.Serum was isolated from another tube of non-anticoagulant whole blood.Its FTO protein was investigated using ELISA,insulin was investigated using chemiluminescence method,and GLU,CHO,TG,HDL-C and LDL-C were investigated by automatic biochemical analyzer.The correlation of the biochemical indicators were analyzed.Results The expression level of FTO mRNA,FTO protein,fasting glucose data,OGTT at 1 h and 2h glucose levels in the case group were 0.17 ％ ± 0.10 ％,61.32 ± 25.23 pg/ml,4.71 ±0.54 mmol/L,10.70±1.36 mmol/L and 8.97 ± 1.60 mmol/L respectively.The values of these biochemical indicators in control group were 0.11％±0.07％,51.47±22.97 pg/ml,4.41± 0.28 mmol/L,8.05±1.04 mmol/L and 6.56±0.75 mmol/L respectively.The differences were statistically significant (t =3.876,2.236,3.817,11.964 and 10.578,P＜0.05).The insulin levels were 6.83±9.76 mU/L in the case group,and 13.15±13.99 mU/L in control group.The differ ences was statistically significant too(t=-2.869,P＜0.05).FTO expression level was positively correlated with FTO protein,OGTT 1h glucose and OGTT 2h glucose levels (r=0.232,0.292,0.242,all P＜0.05),and it was negatively correlated with insulin levels(r=-0.185,P＜0.05).There was no correlation between FTO and fasting glucose expression levels (P ＞0.05).Conclusion The expression of FTO level in pregnant women with GDM was higher than that in healthy pregnant women.The relative expression of FTO mRNA was negatively correlated with insulin.And the regulation of glucose metabolism might be effected by insulin.

Lack of association between genetic polymorphism of FTO, AKT1 and AKTIP in childhood overweight and obesity / Falta de associação entre o polimorfismo genético do FTO, AKT1 e AKTIP e o sobrepeso e a obesidade infantis

Abstract Objective: Obesity is a chronic disease caused by both environmental and genetic factors. Epidemiological studies have documented that increased energy intake and sedentary lifestyle, as well as a genetic contribution, are forces behind the obesity epidemic. Knowledge about the interaction between genetic and environmental components can facilitate the choice of the most effective and specific measures for the prevention of obesity. The aim of this study was to assess the association between the FTO, AKT1, and AKTIP genes and childhood obesity and insulin resistance. Methods: This was a case-control study in which SNPs in the FTO (rs99396096), AKT1, and AKTIP genes were genotyped in groups of controls and obese/overweight children. The study included 195 obese/overweight children and 153 control subjects. Results: As expected, the obese/overweight group subjects had higher body mass index, higher fasting glucose, HOMA-IR index, total cholesterol, low-density lipoprotein, and triglycerides. However, no significant differences were observed in genes polymorphisms genotype or allele frequencies. Conclusion: The present results suggest that AKT1, FTO, and AKTIP polymorphisms were not associated with obesity/overweight in Brazilians children. Future studies on the genetics of obesity in Brazilian children and their environment interactions are needed.

Resumo Objetivo A obesidade é uma doença crônica sustentada por fatores ambientais e genéticos. Estudos epidemiológicos documentaram que maior ingestão de energia e um estilo de vida sedentário, bem como a contribuição genética, são forças por trás da epidemia de obesidade. O conhecimento sobre a interação entre os componentes genéticos e ambientais pode facilitar a escolha das medidas mais efetivas e específicas para a prevenção da obesidade. O objetivo deste estudo foi avaliar a relação entre os genes associado à massa de gordura e à obesidade (FTO), homólogo 1 do oncogene viral v-akt de timoma murino (AKT1) e de ligação AKT1 (AKTIP) e a obesidade infantil e a resistência à insulina. Métodos Estudo de caso-controle no qual os polimorfismos de nucleotídeo simples (SNPs) nos genes FTO (rs99396096), AKT1 e AKTIP foram genotipados em grupos de controle e de crianças obesas/acima do peso. Foram recrutadas 195 crianças obesas/acima do peso e 153 indivíduos controle. Resultados Como esperado, os indivíduos do grupo obeso/acima do peso apresentaram maior índice de massa corporal, maior glicemia de jejum, índice do modelo de avaliação de homeostase (HOMA-IR), colesterol total, lipoproteína de baixa densidade e triglicerídeos. Contudo, não encontramos diferenças significativas no genótipo de polimorfismos gênicos ou nas frequências alélicas. Conclusão Nossos resultados sugerem que os polimorfismos AKT1, FTO e AKTIP não estavam associados à obesidade/sobrepeso em crianças brasileiras. São necessários estudos futuros sobre a genética da obesidade em crianças brasileiras e suas interações ambientais.

Effects of FTO gene on the radiosensitivity of A172 cells and its mechanism / 中华放射医学与防护杂志

Objective To evaluate the effect of Fat Mass and Obesity Associated (FTO) gene on radiosensitivity of human glioma cell A172 and investigate its potential mechanism by changing the expression of FTO gene.Methods Cells were divided into five groups according to their FTO protein expression level.The normal expression group was recorded as A172 Group,the low-expression and its negative control group was A172/siRNA and A172/NC Group,and the over-expression and its negative control group was A172/FTO and A172/PC group.FTO protein expressions were assayed by Western blot in A172 Group after irradiation.Clonogenic assay was executed to evaluate the relationship between FTO gene and radiosensitivity.Immunofluorescence and Western blot assay were applied to detect the proteins of DNA damage and repair.Results FTO protein expression level in A172 Group was significantly related to the irradiation dose and the time post-irradiation.The radiosensitization ratio (SERD0) of A172/siRNA and A172/FTO group were 1.829 and 0.812 respectively.Not only the number of γ-H2AX foci increased (t =-21.884,P ＜ 0.05) in A172/siRNA 1 h post-irradiation but the decreases of p-p95/NBS1 and Ku80 proteins were also detected (t =24.731,23.293,P ＜ 0.05) together with the increase of Rad50 protein (t =3.140,P ＜ 0.05).But the expressions of these proteins in A172/FTO group were opposite to the above phenomenon (t =0.642,-8.364,26.829,P ＜ 0.05).Conclusions FTO gene is a radiation-resistant gene,which may because the regulation of FTO gene could alter the primary injury and DNA damage repair in the irradiated tumor cells.

Relationships between fat mass and obesity associated gene and genetic onset mechanism of obesity in Chinese children / 中华实用儿科临床杂志

Objective To study the association of fat mass and obesity associated gene(FTO gene) and genetic onset mechanism of obesity in Chinese children.Methods Two hundred and one Chinese children with obesity in Beijing Children's Hospital Affiliated to Capital Medical University from Jan.to Sep.2010,were selected as research subjects,183 healthy adult blood donors were selected as normal controls.Mass Spectrometry techniques were used to study the distributions of the alleles and gene type of FTO in patients and controls.And the relationship between FTO gene polymorphism and obesity in Chinese children were studied.Results The distributions of 5 FTO gene polymorphisms (rs9939609A,rs8050136A,rs3751812T,rs1421085C,rs7193144C) in obesity patients and healthy controls had significant differences.And the Haplotype analysis showed that all of the single nucleotide polymorphisms(SNPs) were in linkage disequilibrium,and three out of six (CTGGTCTGG,TCTGCAAAA,CTGGCCTGG) had significant differences between obesity patients and healthy controls (P ＜ 0.05).Conclusions The gene polymorphisms of rs9939609,rs8050136,rs3751812,rs1421085,rs7193144 of FTO gene confer significant susceptibility to obesity in Chinese children.The haplotypes of CTGGTCTGG,TCTGCAAAA,CTGGCCTGG have significant differences between obesity patients and healthy controls.

Association Study of Fat-mass and Obesity-associated Gene and Body Mass Index in Japanese Patients with Schizophrenia and Healthy Subjects

OBJECTIVE: Fat-mass and obesity-associated (FTO) gene is known to be involved in the pathophysiology of obesity and a single-nucleotide polymorphism (SNP) rs9939609 of FTO gene is repeatedly confirmed to be associated with body mass index (BMI) and obesity. The aim of this study is to elucidate effects of FTO gene polymorphism on BMI in Japanese patients with schizophrenia and healthy subjects. METHODS: Three hundred fifty one patients with schizophrenia and 342 age- and sex-matched healthy subjects participated in the study. Information on BMI and antipsychotic medication was also collected from patients and healthy subjects. Genotype of the FTO SNP rs9939609 was determined by TaqMan SNP Genotyping Assays. RESULTS: There was no significant difference in BMI between patients and healthy subjects. No significant difference in BMI was observed among any medications. We observed no significant difference in rs9939609 allele frequencies between patients and healthy subjects. There was a significant difference in BMI between healthy subjects with risk (AA or TA) genotypes and those with TT genotype. We also observed a significant positive correlation between the number of risk allele (A allele) and BMI in healthy subjects. CONCLUSION: Our study suggested that FTO rs9939609 polymorphism might have some impacts on the BMI in healthy subjects, but might not have same impacts on the BMI of patients with schizophrenia.

Impact on the risk of obesity due to interactions between fat mass- and obesity-associated gene rs9939609 variants and behavioral factors, in the Chinese school-aged children / 中华流行病学杂志

Objective To investigate how the interactions between fat mass- and obesityassociated (FTO) gene rs9939609 variants and daily-life related behavioral factors would influence the risk of obesity among the Chinese school-aged children. Methods 3503 school-aged children were selected from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) Study, and divided into obese children (n=1229) and non-obese children (n=2274). Venipuncture blood test,genotyping and questionnaire were performed. Results Five common factors including protein foods, tobacco & alcohol, vegetables & fruits, sedentary behavior and physical exercise in spare time were extracted with factor analysis methodology. Data from logistic regression analysis showed that taking the interaction of rs9939609 variant with protein foods as an example, the risk of interaction accounted for 19.16% when both factors existing simultaneously. Similarly, the interactions of this SNP with vegetables & fruits, sedentary behavior and physical exercise in spare time appeared to be 5.97%, 19.62% and 12.43% respectively; however there might not be interaction between tobacco,alcohol and the SNP in the Chinese children. Conclusion Protein foods, vegetables & fruits,sedentary behavior and physical exercise might modify the effects of FTO rs9939609 variant on the risk of obesity in Chinese school-aged children. However, large-scale, prospective studies with detailed information on related behavioral factors would be ideal models for identifying the interactions between genes and environment.