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.
Adipocytes ; Adipogenesis/genetics* ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Animals ; Obesity/genetics* ; RNA, Messenger/genetics*

Obesity-associated protein (FTO) is an important m6A demethylase that regulates RNA methylation modification and can promote the proliferation of acute myeloid leukemia(AML) cells. FTO regulates the methylation level of AML through multiple cellular signaling pathways such as FTO/RARA/ASB2, FTO/m6A/CEBPA, and PDGFRB/ERK, and participates in the occurrence, development, treatment and prognosis of AML. At present, studies have found that a variety of inhibitors targeting FTO have shown good anti-leukemia effects, and the study of FTO will provide new ideas for the treatment of AML. This review focus on the mechanism of action of FTO in AML and the research progress of FTO inhibitors in AML.
Humans ; Methylation ; Leukemia, Myeloid, Acute/genetics* ; Prognosis ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism*

OBJECTIVETo clarify the contradictory findings in patients with obesity and type 2 diabetes by meta-analysis.

METHODSPubMed and Embase were searched for articles published up to March 2009. All studies on the association of FTO polymorphisms with obesity and type 2 diabetes were included. Pooled odds ratio was calculated using the model of fixed or random effects. Sensitivity analysis was performed to evaluate the stability of meta-analytic results.

RESULTSMeta-analysis suggested that rs9939609 A allele was more significantly associated with obesity risk than T allele (3 studies / 004 cases and 4544 control subjects): random effect odds ratio (OR)=1.28, 95%CI=1.05 and 1.55, P heterogeneity =0.05, I2=66.6%. Similar results were observed in rs8050136 polymorphism (3 studies/2404 cases and 5713 control subjects): fixed effect OR =1.25, 95%CI=1.13, 1.37, P heterogeneity=0.12, I2=51.9%. However, no significant association was found between genetics and risk of type 2 diabetes after control of potential confounders (at least for BMI) either for rs9939609 (fixed effect OR=1.05, 95% CI=0.97,1.13) or for rs8050136 polymorphism (fixed effect OR =1.07, 95%CI: 0.99, 1.16). Furthermore, the sensitivity analysis strengthened our confidence in validity of the association. Conclusion FTO polymorphisms are associated with obesity but not with type 2 diabetes in East Asian populations. Further large-scale studies are required to conclusively establish the association.

Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Asian Continental Ancestry Group ; genetics ; Diabetes Mellitus, Type 2 ; genetics ; Far East ; Humans ; Obesity ; genetics ; Proteins ; genetics ; metabolism

Obesity is a great risk factor for type 2 diabetes and certain types of cancer, which become a major burden for public health worldwide. As a classic complex disease, obesity is regarded as the interaction of genetic and environmental factors. However, it is controversial which of these two factors have greater effect on obesity. Several genetic loci have recently been reported to contribute to the development of obesity reported in genome-wide association study (GWAS) these years. GWAS play an important role in complex disease research and explore the potential effect of genetic variance. To further understand the genetic influence on obesity risk, we reviewed and collected articles on Pubmed for genes that reported in recent GWAS. We summarized the publications in GWAS and found 49 candidate genes, which were strongly suggested to relate to obesity risk in human. Despite the findings of this and other similar, contemporary research projects, much of the single nucleotide polymorphism details and underlying mechanism in this field of study remains, to a great extent, unknown. As a result, future studies are needed for obesity risk in human beings.
Aldose-Ketose Isomerases ; genetics ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Brain-Derived Neurotrophic Factor ; genetics ; Genome-Wide Association Study ; trends ; Humans ; Obesity ; genetics ; physiopathology ; Polymorphism, Single Nucleotide ; Proteins ; genetics

BACKGROUND: There are only limited numbers of reviews on the association of maternal-child genetic polymorphisms and environmental and lifestyle-related chemical exposure during pregnancy with adverse fetal growth. Thus, this article aims to review: (1) the effect of associations between the above highlighted factors on adverse fetal growth and (2) recent birth cohort studies regarding environmental health risks. METHODS: Based on a search of the PubMed database through August 2021, 68 epidemiological studies on gene-environment interactions, focusing on the association between environmental and lifestyle-related chemical exposure and adverse fetal growth was identified. Moreover, we also reviewed recent worldwide birth cohort studies regarding environmental health risks. RESULTS: Thirty studies examined gene-smoking associations with adverse fetal growth. Sixteen maternal genes significantly modified the association between maternal smoking and adverse fetal growth. Two genes significantly related with this association were detected in infants. Moreover, the maternal genes that significantly interacted with maternal smoking during pregnancy were cytochrome P450 1A1 (CYP1A1), X-ray repair cross-complementing protein 3 (XRCC3), interleukin 6 (IL6), interleukin 1 beta (IL1B), human leukocyte antigen (HLA) DQ alpha 1 (HLA-DQA1), HLA DQ beta 1 (HLA-DQB1), and nicotinic acetylcholine receptor. Fetal genes that had significant interactions with maternal smoking during pregnancy were glutathione S-transferase theta 1 (GSTT1) and fat mass and obesity-associated protein (FTO). Thirty-eight studies examined the association between chemical exposures and adverse fetal growth. In 62 of the 68 epidemiological studies (91.2%), a significant association was found with adverse fetal growth. Across the studies, there was a wide variation in the analytical methods used, especially with respect to the genetic polymorphisms of interest, environmental and lifestyle-related chemicals examined, and the study design used to estimate the gene-environment interactions. It was also found that a consistently increasing number of European and worldwide large-scale birth cohort studies on environmental health risks have been conducted since approximately 1996. CONCLUSION There is some evidence to suggest the importance of gene-environment interactions on adverse fetal growth. The current knowledge on gene-environment interactions will help guide future studies on the combined effects of maternal-child genetic polymorphisms and exposure to environmental and lifestyle-related chemicals during pregnancy.
Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Female ; Fetal Development ; Gene-Environment Interaction ; Humans ; Life Style ; Maternal Exposure/adverse effects* ; Polymorphism, Genetic ; Pregnancy

OBJECTIVE: To investigate the down-regulation effect of let-7b-5p on the expression of FTO in acute myeloid leukemia cell line THP-1 and inhibitory effect on THP-1 proliferation via m METHODS: The acute myeloid leukemia cell line THP-1 and the normal human peripheral blood mononuclear cells (PBMNC) were selected as subjects. The expression of let-7b-5p and FTO mRNA in those cells was detected by qPCR, further the expression of FTO protein in those cells was detected by Western blot. And, the luciferase reporter gene assay was used to verify the targeting effect of let-7b-5p on FTO. Finally, THP-1 cells were transfected respectively with let-7b-5p mimic, and PBMNC with let-7b-5p inhibitor, there after the C-MYC mRNA m RESULTS: Compared with PBMNC, the expression of let-7b-5p in THP-1 significantly decreased, while the expression of FTO was significantly increased (P<0.05). After transfection with let-7b-5p mimic combined with FTO 3'-UTR, the luciferase activity of transfected THP-1 cells significantly decreased, but the luciferase activity significantly increased after transfection with mutant 3'-UTR, which was significantly different from the negative control group(blank vector) (P<0.05). Let-7b-5p inhibitor down-regulated c-MYC mRNA m CONCLUSION Human acute myeloid leukemia cell line THP-1 low expresses the let-7b-5p, which regulates c-MYC expression through let-7b-5p-/FTO-/m
Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics* ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Leukemia ; Leukocytes, Mononuclear ; MicroRNAs/genetics* ; Signal Transduction ; THP-1 Cells

Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; genetics ; Body Mass Index ; Body Weight ; genetics ; physiology ; Female ; Genotype ; Homeodomain Proteins ; genetics ; Humans ; Male ; Obesity ; genetics ; metabolism ; Transcription Factors ; genetics

Recent studies have unequivocally established the link between FTO and obesity. FTO was biochemically shown to belong to the AlkB-like family DNA/RNA demethylase. However, FTO differs from other AlkB members in that it has unique substrate specificity and contains an extended C-terminus with unknown functions. Insight into the substrate selection mechanism and a functional clue to the C-terminus of FTO were gained from recent structural and biochemical studies. These data would be valuable to design FTO-specific inhibitors that can be potentially translated into therapeutic agents for treatment of obesity or obesity-related diseases.
AlkB Homolog 1, Histone H2a Dioxygenase ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Amino Acid Motifs ; Animals ; Catalytic Domain ; DNA ; metabolism ; DNA Repair Enzymes ; metabolism ; Humans ; Methylation ; Obesity ; genetics ; Proteins ; chemical synthesis ; classification ; genetics ; RNA ; metabolism ; Substrate Specificity

OBJECTIVETo study the association of rs9939609 polymorphism of the fat mass and obesity associated gene (FTO) with overweight or obesity in Hazakh children.

METHODSPCR-restriction fragment length polymorphism was used to determine the rs9939609 polymorphism in 141 patients with overweight or obesity and 138 healthy controls. Height and weight were measured for body mass index (BMI). Serum lipid levels including total cholesterol, triglyceride, high-density and low-density lipoprotein cholesterol, blood pressure, plasma glucose levels, and plasma insulin were also determined.

RESULTSThe genotype distributions of both groups were in the Hardy-Weinberg equilibrium. The frequencies of AA, AT and TT were 0.071, 0.511 and 0.418 in the overweight or obesity group, and 0.029, 0.428 and 0.543 in the controls (Chi-square = 5.74, P= 0.057). However, the frequency of AA+ AT genotype in case group (0.582, 82/141) was higher than that in the controls (0.457, 63/138)(Chi-square = 4.368, P= 0.037). The A allele frequency in the case group (0.326) was higher than that in the controls (0.243) (Chi-square = 4.772, P= 0.029). In both groups, the plasma glucose levels of individuals with AA+ AT genotype (4.88± 0.51 mol/L) was higher than those with TT genotypes (4.68± 0.56 mol/L)(P= 0.026). Logistic regression analysis showed that the A allele of the FTO gene was an independent risk factor for overweight or obesity (OR= 0.527; 95%CI: 0.319-0.869).

CONCLUSIONThe A allele of the fat mass and obesity associated gene might be a risk factor of overweight or obesity in Hazakh children in Xinjiang.

Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Analysis of Variance ; Case-Control Studies ; Child ; China ; ethnology ; Ethnic Groups ; genetics ; Female ; Gene Frequency ; Genotype ; Humans ; Male ; Obesity ; blood ; genetics ; metabolism ; physiopathology ; Phenotype ; Polymorphism, Genetic ; genetics ; Proteins ; genetics

BACKGROUNDGenome-wide association studies for type 2 diabetes mellitus (T2DM) identified FTO gene as a locus conferring increased risk for common obesity in many populations with European ancestry. However, the involvement of FTO gene in obesity or T2DM related metabolic traits has not been consistently established in Chinese populations. The objective of this study was to investigate the association of FTO genetic polymorphisms with metabolic syndrome (MetS) in Han Chinese.

METHODSWe tested 41 FTO single nucleotide polymorphisms (SNPs) for association between FTO and MetS-related traits. There were a total of 236 unrelated subjects (108 cases and 128 controls), grouped according to the International Diabetes Federation (IDF) criteria.

RESULTSOf the 41 SNPs examined, only SNP rs8047395 exhibited statistical significance (P = 0.026) under a recessive model, after Bonferroni adjustment for multiple testing (OR 1.64, 95%CI 1.11-2.42; P = 0.014). The common distributions of this polymorphism among Chinese--with a minor allele frequency (MAF) of 36% in the control group versus 48% in the MetS group--greatly improved our test power in a relatively small sample size for an association study. Previously identified obesity- (or T2DM-) associated FTO SNPs were less common in Han Chinese and were not associated with MetS in this study. No significant associations were found between our FTO SNPs and any endophenotypes of MetS.

CONCLUSIONSA more common risk-conferring variant of FTO for MetS was identified in Han Chinese. Our study substantiated that genetic variations in FTO locus are involved in the pathogenesis of MetS.

Alpha-Ketoglutarate-Dependent Dioxygenase FTO ; Asian Continental Ancestry Group ; Female ; Genetic Predisposition to Disease ; genetics ; Genetic Variation ; genetics ; Genotype ; Haplotypes ; genetics ; Humans ; Male ; Metabolic Syndrome ; genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; genetics ; Proteins ; genetics