Fat Mass And Obesity-associated Research Articles

Assessment of health risks caused by overweight in children depending on the FTO gene rs9939609 polymorphism

In this study, we aimed to estimate the association between the rs9939609 FTO (fat mass and obesity associated) polymorphism and a risk of overweight in children living in the Baikal region. We performed a case – control study that included 113 schoolchildren living in industrial centers of the Baikal region (Irkutsk, Angarsk, and Ulan-Ude). Anthropometric parameters were measured and body mass index was calculated with its values being ranked in accordance with the WHO BMI curves depending on a sex and age. Genotyping of the rs9939609 FTO polymorphism was performed by allele-specific amplification with real-time results detection. To assess likelihood of an association between the FTO gene allele and overweight and obesity, relative risk (RR) and 95 % confidence interval (CI) were calculated. The assessment revealed the A allele of the rs9939609 FTO polymorphism to be by 1.29 times more frequent in the examined children with overweight and obesity (48.44 %) than in the children form the reference group (37.65 %). The FTO rs9939609 polymorphism was authentically associated with likelihood of elevated risks of overweight and obesity in children with the homozygous AA genotype (RR = 2.806, 95 % CI: 1.650–4.772; STD = 0.271). Our study confirms that the rs9939609 polymorphism of the FTO gene is a risk factor of overweight and obesity for children from the Baikal region who have the A allele of the homozygous AA genotype. Prevailing frequency of the TT genotype (29.2 %) as compared with the AA genotype (10.62) is likely due to influence of assimilation processes on urbanized territories in the Baikal region.

Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease.

Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age-related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD. To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome-wide association study (GWAS) of fat free mass index (FFMI) in 32 426 non-Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity-associated (FTO) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (n=3656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes. Multiple SNPs located in the FTO gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene AC090771.2, which transcribes long non-coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A>T in the FTO gene (β=0.151, SE=0.021, P=1.40×10-12 for UK Biobank |β=0.220, SE=0.041, P=9.99×10-8 for COPDGene) and chr 18 SNP rs11664369C>T nearest to the AC090771.2 gene (β=0.129, SE=0.024, P=4.64×10-8 for UK Biobank |β=0.203, SE=0.045, P=6.38×10-6 for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of FTO lowered myotube diameter and induced a senescence-associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia. Genetic polymorphisms of FTO and AC090771.2 were associated with sarcopenia in COPD in independent cohorts. Knockdown of FTO in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD.

Оценка риска избыточной массы тела у детей в зависимости от полиморфизма rs9939609 генa FTO

In this study, we aimed to estimate the association between the rs9939609 FTO (fat mass and obesity associated) polymorphism and a risk of overweight in children living in the Baikal region. We performed a case – control study that included 113 schoolchildren living in industrial centers of the Baikal region (Irkutsk, Angarsk, and Ulan-Ude). Anthropometric parameters were measured and body mass index was calculated with its values being ranked in accordance with the WHO BMI curves depending on a sex and age. Genotyping of the rs9939609 FTO polymorphism was performed by allele-specific amplification with real-time results detection. To assess likelihood of an association between the FTO gene allele and overweight and obesity, relative risk (RR) and 95 % confidence interval (CI) were calculated. The assessment revealed the A allele of the rs9939609 FTO polymorphism to be by 1.29 times more frequent in the examined children with overweight and obesity (48.44 %) than in the children form the reference group (37.65 %). The FTO rs9939609 polymorphism was authentically associated with likelihood of elevated risks of overweight and obesity in children with the homozygous AA genotype (RR = 2.806, 95 % CI: 1.650–4.772; STD = 0.271). Our study confirms that the rs9939609 polymorphism of the FTO gene is a risk factor of overweight and obesity for children from the Baikal region who have the A allele of the homozygous AA genotype. Prevailing frequency of the TT genotype (29.2 %) as compared with the AA genotype (10.62) is likely due to influence of assimilation processes on urbanized territories in the Baikal region.

Effects of Helicobacterpylori on the expression of the FTO gene and its biological role in gastric cancer.

Helicobacter pylori (Hp) is a primary risk factor for gastric cancer. The fat mass and obesity-associated (FTO) gene is associated with the development and progression of various cancer types such as glioma, leukemia, breast cancer and colorectal cancer. The aim of the present study was to investigate the effect of Hp infection on the expression of FTO and its roles in gastric cancer. It was found that the expression levels of both FTO mRNA and protein were significantly increased in Hp-infected human gastric mucosal epithelial cells and Mongolian gerbil gastric tissues. The expression of FTO in gastric cancer tissues was higher than that in para-cancer tissues. Data from The Cancer Genome Atlas demonstrated that FTO expression in gastric cancer tissues was significantly higher than that in normal tissues. Patient survival rate was significantly decreased in patients with high expression levels of FTO. It was also demonstrated that FTO expression was associated with several pathological parameters, such as tumor stage, metastasis stage and the American Joint Committee on Cancer stage. The FTO gene was positively correlated with 16,601 genes in gastric cancer and negatively correlated with 3,623 genes. Gene Ontology enrichment analysis demonstrated that FTO was significantly enriched in the regulation of gene expression and oxidative RNA demethylase activity, and it was associated with components such as the RNA N6-methyladenosine methyltransferase complex and nuclear speckle. In addition, knockdown of the FTO gene inhibited the migration and invasion of Hp-infected cells. In conclusion, the data suggests that Hp infection leads to upregulation of the FTO gene, which may be related to patient survival rate, tumor staging and other pathological parameters of patients with gastric cancer. It also suggests that FTO promotes proliferation and migration of gastric cancer cells, which may be involved in the pathogenesis of Hp-induced gastric cancer.

Syntheses and Molecular Docking Analysis of Some New Thiazole and Thiazine Derivatives as Three Armed Molecules with a Triazine Ring as a Core Component: A Search for anti-Obesity Agents

A number of new three-armed heterocycles as thiazoles and thiazines linked to triazine moiety was prepared starting from cyanuaric chloride and thiothemicarbazide which gave the target compound 1. The reaction of the tris-thiosemicarbazide with a variety of hydrazonoyl halides afforded thiazole derivatives. In addition, a thiazole derivative could be prepared from the reaction of the target compound 1 with DMAD. Moreover, thiazine derivatives were synthesized from compound 1 through its interaction with benzylidinemalonitrile. In this work, the molecular docking analysis of thirteen compounds against FTO (Fat mass and Obesity-Associated) protein is carried out to investigate the mode of their molecular interactions. Furthermore, in silico ADMET predictions for the new compounds were calculated with the objective to gain an insight into their pharmacokinetic, safety, and drug-likeness profile. The new compounds could be promising chemical scaffolds for the development of future anti-obesity drug candidates.

Screening of Exons 4-9 Polymorphisms of FTO Gene in Endometrial and Ovarian Cancers.

Endometrial and ovarian tumours are almost mechanistically affected by reproductive hormones. Ovarian cancer may be explained as metastatic or synchronous primary ovarian cancer, and the specific diagnosis is a challenge. This study aimed to investigate the mutations in fat mass and obesity-associated (FTO) genes and investigated the association of these mutations with the risk of endometrial and ovarian cancers as well as with cancer grade and stage. Blood samples were collected from 48 endometrial and ovarian cancer cases and 48 healthy women. Genomic DNA was extracted, and PCR was done to amplify FTO exons 4-9. Sanger sequencing identified 6 different novel mutations submitted to DDBJ: p.W278G and p.G284G in exon 4, p.S318I and p.A324G in exon 5 and two mutations in intron 4. Other mutations were also detected in FTO gene sequencing results, rs112997407 in intron 3, rs62033438, rs62033439, rs8048254 and rs8046502 in intron 4. The novel p.W278G, p.S318I and p.A324G mutations were predicted to be damaging. We did not find a significant association for all variables with cancer risk or clinical stage and grade except for rs62033438 variants, which showed a significant association with cancer grade, especially AA genotype (OR= 15, 95% CI:1.32 -169.88, P= 0.03). In conclusion, the statistical analysis did not clarify whether FTO mutations are implicated in cancer. Further studies with more samples are recommended to provide a more accurate picture of the correlation between FTO mutations and endometrial and ovarian cancer susceptibility.

The Role of RNA Epitranscriptomics and the RNA Fat Mass and Obesity-Associated Demethylase in Triple Negative Breast Cancer

Breast cancer is one of the most commonly diagnosed cancers and one of the most significant sources of cancer mortality. Triple negative breast cancer (TNBC) is a particularly aggressive subtype that has proven difficult to treat with standard chemotherapies. Obesity has also been shown to exacerbate breast cancer, and diagnoses of these two diseases frequently overlap. Both conditions are regulated in part by the fat mass and obesity-associated (FTO) demethylase, an RNA demethylase which may drive breast cancers through epigenetic alterations to gene expression. Methods of inhibiting FTO have been researched in vitro and in vivo as an alternative or adjunct to chemotherapies in multiple cancers, including breast cancer. Translating knowledge of the role of FTO in breast cancer and the development of novel agents may allow for improvements in the treatment of this refractory cancer. This review therefore aims to provide an overview of existing and developing chemical inhibitors of FTO that could be innovatively studied for the treatment of TNBC and associated comorbidity.

Association of lipid metabolism-related metabolites with overweight/obesity based on the FTO rs1421085.

Globally, obesity is a severe health issue. A more precise and practical approach is required to enhance clinical care and drug development. The FTO (fat mass and obesity-associated) gene variant rs1421085 is strongly associated with an increased susceptibility to obesity in numerous populations; however, the precise mechanism behind this association concerning metabolomics is still not understood. This study aims to examine the association between metabolites and obesity-related anthropometric traits based on the variant FTO rs1421085. This study was based on a case-control design involving a total of 542 participants including overweight/obese cases and healthy controls. The blood samples were collected from all the participants. The isolated serum samples were subjected to untargeted metabolomics using GC-MS. The isolated DNA samples were genotyped for the FTO rs1421085 variant. Initially, a total of 42 metabolites were identified on GC-MS, which were subjected to further association analyses. The study observed a significant association of two metabolites, glycerol and 2,3-dihydroxypropyl stearate with FTO gene variant rs1421085 and obesity-related anthropometric traits including % BF, WHtR, WC, and HC. The CT genotype of FTO rs1421085 may greatly increase the risk of overweight/obesity by changing the lipid metabolism-related metabolites. Therefore, this study highlights the significance of biochemical networks in the progression of obesity in carriers of the FTO rs1421085 risk genotype.

Antiobesity potential of major metabolites from Clitoria ternatea kombucha: Untargeted metabolomic profiling and molecular docking simulations

The prevalence of obesity is rapidly increasing and poses serious health risks accompanied by a decrease in life expectancy and quality of life. Therefore, the therapeutic potential of natural-derived nutraceuticals against obesity and its comorbidities needs to be explored. Molecular inhibition of lipase enzymes and fat mass and obesity-associated (FTO) protein has attracted some recent interest in efforts to find antiobesity agents. This study aims to innovate a fermented drink from Clitoria ternatea kombucha (CTK), find out their metabolites profile, and determine the antiobesity potential through a molecular docking study. The CTK formulation refers to previous research while the metabolites profile was determined using HPLC-ESI-HRMS/MS. Major compounds were selected based on best match value > 99.0% of the M/Z cloud database. A total of 79 compounds were identified in CTK, and 13 ideal compounds were selected to be simulated in the molecular docking study against human pancreatic lipase, α-amylase, α-glucosidase, porcine pancreatic lipase, and FTO proteins. The study found that Kaempferol, Quercetin-3β-D-glucoside, Quercetin, Dibenzylamine, and α-Pyrrolidinopropiophenone showed the best potential as functional antiobesity compounds since their affinity value ranked high in each respective receptor. In conclusion, the major compounds of CTK metabolites have the potential to be promising functional foods against obesity. However, further in vitro and in vivo studies should validate these health benefits.

The Influence of Fat Mass and Obesity-Associated (FTO) Gene on the Effect of Physical Activity (PA) on Risk of Obesity: Scoping Review

The Influence of Fat Mass and Obesity-Associated (FTO) Gene on the Effect of Physical Activity (PA) on Risk of Obesity: Scoping Review

Pyrido-pyrimido-thiadiazinones: green synthesis, molecular docking studies and biological investigation as obesity inhibitors

Obesity is a global public health concern brought on by a combination of excessive dietary intake, inactivity and genetic predisposition. Pyridopyrimidines have received considerable interest in the development of obesity and diabetes. Mannich reaction was applied on 2-thioxo-pyridopyrimidinone derivative with a variety of aromatic and heterocyclic aromatic amines and formaldehyde by grinding at 25°C in the presence of HCl to obtain 18 fused thiadiazinones and two bis-fused thiadiazinone derivatives. Additionally, in silico docking was performed to investigate the mode of actions of the 20 synthesized compounds against fat mass and obesity-associated (FTO) protein. The ligand molecules are nicely docked to the target FTO with binding energies (ΔGbind) ranging from −11.6 to −8.0 kcal/mol. Electrostatic potential map of semiempirical optimized compound 16 was performed using Gaussian 03. Interestingly, two bis-fused thiadiazinone derivatives showed marked amelioration of adiposity in the high-fat diet model especially in hepatic and adipose tissues.

M6A demethylase FTO regulate CTNNB1 to promote adipogenesis of chicken preadipocyte

BackgroundN6-methyladenosine (m6A) is an abundant post-transcriptional RNA modification that affects various biological processes. The fat mass and obesity-associated (FTO) protein, a demethylase encoded by the FTO gene, has been found to regulate adipocyte development in an m6A-dependent manner in multiple species. However, the effects of the m6A methylation and FTO demethylation functions on chicken adipogenesis remain unclear. This study aims to explore the association between m6A modification and chicken adipogenesis and the underlying mechanism by which FTO affects chicken preadipocyte development.ResultsThe association between m6A modification and chicken lipogenesis was assessed by treating chicken preadipocytes with different doses of methyl donor betaine and methylation inhibitor cycloleucine. The results showed that betaine significantly increased methylation levels and inhibited lipogenesis, and the inverse effect was found in preadipocytes after cycloleucine treatment. Overexpression of FTO significantly inhibited m6A levels and promoted proliferation and differentiation of chicken preadipocytes. Silencing FTO showed opposite results. Mechanistically, FTO overexpression increased the expression of catenin beta 1 (CTNNB1) by improving RNA stability in an m6A-dependent manner, and we proved that FTO could directly target CTNNB1. Furthermore, CTNNB1 may be a positive regulator of adipogenesis in chicken preadipocytes.Conclusionsm6A methylation of RNA was negatively associated with adipogenesis of chicken preadipocytes. FTO could regulate CTNNB1 expression in a demethylation manner to promote lipogenesis.

Fat mass and Obesity Associated (FTO) gene and polycystic ovary syndrome: Insight into pathogenesis and association with insulin resistance

Fat mass and Obesity Associated (FTO) gene and polycystic ovary syndrome: Insight into pathogenesis and association with insulin resistance

Effect of green cardamom on the expression of genes implicated in obesity and diabetes among obese women with polycystic ovary syndrome: a double blind randomized controlled trial

BackgroundPolycystic ovary syndrome (PCOS) is an endocrine disease in which related to obesity, metabolic disorders and is considered as one of the main causes of infertility in women. This trial was investigated the effects of green cardamom on the expression of genes implicated in obesity and diabetes among obese women with PCOS.MethodsOne hundred ninety-four PCOS women were randomly divided two groups: intervention (n = 99; 3 g/day green cardamom) and control groups (n = 95). All of them were given low calorie diet. Anthropometric, glycemic and androgen hormones were assessed before and after 16-week intervention. The reverse transcription-polymerase chain reaction (RT-PCR) method was used to measure fat mass and obesity-associated (FTO), peroxisome proliferative activating receptor- (PPAR-), carnitine palmitoyltransferase 1A (CPT1A), acetyl-CoA carboxylase beta (ACAB), leptin receptor (LEPR), ghrelin, and lamin A/C (LAMIN) genes expression in each group.ResultsAnthropometric indices were significantly decreased after intervention in both two studied groups. Glycemic indices and androgen hormones were significantly improved in the intervention group compared to the control group. The expression levels of FTO, CPT1A, LEPR, and LAMIN were significantly downregulated compared to control group (P < 0.001), as well as, PPAR-y was significantly upregulated in the intervention group after intervention with green cardamom compared to control group (P < 0.001).ConclusionThis current study showed that the administration of green cardamom is a beneficial approach for improving anthropometric, glycemic, and androgen hormones, as well as obesity and diabetes genes expression in PCOS women under the low-calorie diet.Trial registrationThis trial was registered with the Iranian Clinical Trials Registry (registration number: IRCT20200608047697N1). 1 August, 2020; https://www.irct.ir/trial/48748

Genes Predisposing to Monogenic, Polygenic, and Syndromic Obesity: A Review of Current Trends and Prospects for Standard Obesity Genetic Testing

Objective: The burden of obesity is currently enormous, necessitating a novel strategy to complement the existing ones. Accordingly, genetic predisposition is suspected in many cases of the disease, which can potentially be used as therapeutic targets. However, there are differing viewpoints on the suspect genes, prompting the current review to articulate the genes and their mechanisms. Eight (16%) of the genes singularly predispose humans to obesity (called monogenic obesity), 22 (43%) interact with other genes and the environment to predispose humans to obesity (called polygenic obesity), and 21 (41%) cause syndromic obesity. Monogenic obesity is often caused by three genes [the leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) genes], polygenic obesity [fat mass and obesity-associated (FTO) gene], and syndromic obesity (Prader-Willi Syndrome). These genes control food intake and energy expenditure, and so mutations in them cause overeating, adiposity, and hyperphagia. Based on these findings, two geneticallybased drugs, named recombinant human leptin and setmelanotide, have been formulated and shown to significantly reduce food intake, body weight, and fat mass. This suggests that when the genetic etiology of obesity is fully understood, the disease’s treatment and prevention will improve. Healthcare providers are urged to develop genetically-based personalized treatments for obese patients.

The role of FTO variant rs1421085 in the relationship with obesity: a systematic review and meta-analysis.

Fat mass and obesity-associated (FTO) is considered the first locus associated with adiposity, a concerning health problem worldwide. Many studies have evaluated the relationship between the FTO variants and obesity susceptibility. While the strong association of FTO rs1421085 with the risk of obesity across populations was reported in different studies, some researchers found a lack of association of this variant with adiposity. This systematic review and meta-analysis aimed to assess the association between obesity and rs1421085 polymorphism. We systematically searched PubMed, Scopus, and Google Scholar up to June 2022 to find pertinent studies. To further assess this issue, we surveyed the probable association of rs1421085 with obesity development among Iranian adults using the logistic regression analysis, and the obtained results were used for doing meta-analysis. After selection, nine eligible studies were included in the meta-analysis through the random- and fixed-effect models to determine the combined odds ratios (OR) and 95% confidence intervals (CI). According to our meta-analysis conducted on 5169 obese and 7772 non-obese individuals using different genetic models, including recessive, dominant, over-dominant, and additive, rs1421085 could positively increase the risk of obesity under all tested genetic models. Also, we detected a high to moderate level of heterogeneity among different studies under various genetic models. This meta-analysis further verified the positive association of FTO rs1421085 with the risk of developing obesity. This study is registered as PROSPERO CRD42021220092. Level I, systematic reviews and meta-analyses.

The effects of FTO gene rs9939609 polymorphism on the association between breast cancer and dietary intake.

Breast cancer (BC) is the leading cause of cancer-related deaths in females worldwide and is related to genetic and environmental factors. Dietary components may strongly influence the risk of BC. A possible association was also reported between the fat mass and obesity-associated (FTO) single-nucleotide polymorphisms (SNPs) and BC. This study aimed to investigate the impact of FTO rs9939609 polymorphism on the association between BC and dietary intake. This study was conducted on 180 women with BC as the case group and 360 healthy women as the control group. The dietary intakes were assessed by a valid 168-item food frequency questionnaire (FFQ). The FTO gene was genotyped for rs9939609 polymorphism. After adjusting the confounding variables, there was no significant association between dietary intake and BC in individuals without risk allele. A positive association between dietary intake of omega-6 fatty acids and BC was found only in individuals with risk allele of FTO gene (OR: 1.31, 95% CI: 1.08-1.60, p: 0.006). FTO gene risk allele may influence the effect of diet on breast cancer risk. Further studies are needed to assess the possible effects of the FTO genotype on the association between BC risk and dietary components.

Fat mass and obesity-associated protein alleviates Aβ1-40 induced retinal pigment epithelial cells degeneration via PKA/CREB signaling pathway.

Amyloid-β (Aβ) is thought to be a critical pathologic factor of retinal pigment epithelium (RPE) degeneration in age-related macular degeneration (AMD). Aβ induces inflammatory responses in RPE cells and recent studies demonstrate the N6-methyladenosine (m6A) regulatory role in RPE cell inflammation. m6A is a reversible epigenetic posttranslational modification, but its relationship with Aβ-induced RPE degeneration is yet to be thoroughly investigated. The present study explored the role and mechanism of m6A in Aβ-induced RPE degeneration model. This model was induced via intravitreally injecting oligomeric Aβ and the morphology of its retina was analyzed. One of m6A demethylases, the fat mass and obesity-associated (FTO) gene expression, was assessed. An m6A-messenger RNA (mRNA) epitranscriptomic microarray was employed for further bioinformatic analyses. It was confirmed that Aβ induced FTO upregulation within the RPE. Hypopigmentation alterations and structural disorganization were observed in Aβ-treated eyes, and inhibition of FTO exacerbated retinal degeneration and RPE impairment. Moreover, the m6A-mRNA epitranscriptomic microarray suggested that protein kinase A (PKA) was a target of FTO, and the PKA/cyclic AMP-responsive element binding (CREB) signaling pathway was involved in Aβ-induced RPE degeneration. m6A-RNA binding protein immunoprecipitation confirmed that FTO demethylated PKA within the RPE cells of Aβ-treated eyes. Altered expression of PKA and its downstream targets (CREB and brain-derived neurotrophic factor) was confirmed by quantitative reverse-transcription polymerase chain reaction and Western blot analyses. Hence, this study's findings shed light on FTO-mediated m6A modification in Aβ-induced RPE degeneration and indicate potential therapeutic targets for AMD.

Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and increasing the stability of SREBF1 and ChREBP mRNAs.

Previous studies have indicated an association of fat mass and obesity-associated (FTO) with nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. This study aimed to decipher the complex role of FTO in hepatic lipid metabolism. We found that a decrease in N6-methyladenosine (m6A) RNA methylation in the liver of mice fed with a high-fat diet (HFD) was accompanied by an increase in FTO expression. Overexpression of FTO in the liver promoted triglyceride accumulation by upregulating the expression of lipogenic genes. Mechanistical studies revealed that FTO could stabilize the mRNAs of sterol regulatory element binding transcription factor 1 (SREBF1) and carbohydrate responsive element binding protein (ChREBP), two master lipogenic transcription factors, by demethylating m6A sites. Knockdown of either SREBF1 or ChREBP attenuated the lipogenic effect of FTO, suggesting that they are bona fide effectors for FTO in regulating lipogenesis. Insulin could stimulate FTO transcription through a mechanism involving the action of intranuclear insulin receptor beta, while knockdown of FTO abrogated the lipogenic effect of insulin. Inhibition of FTO by entacapone decreased the expression of SREBF1, ChREBP, and downstream lipogenic genes, ameliorating liver steatosis in HFD-fed mice. Thus, our study established a critical role of FTO in both the insulin-regulated hepatic lipogenesis and the pathogenesis of NAFLD and provided a potential strategy for treating NAFLD.

The Effect of Association between Fat Mass and Obesity-associated Gene Polymorphism (rs9939609) on the Body Composition of Older People: A Systematic Review.

The aging population is growing faster than any other age group worldwide. Associated with aging, the prevalence of overweight and obesity is a potential risk factor for the development and aggravation of numerous pathologies. A genetic factor often associated with obesity is the fat mass and obesity-associated (FTO) (rs9939609) gene polymorphism, which has been extensively investigated in children, young, and adults. However, few studies have been carried out on the older population. This review aimed to verify the influence of the FTO (rs9939609) gene polymorphism on the body composition of the older population. We conducted a systematic review and meta-analysis on PubMed, Scielo, and LILACS databases. Statistical analysis for meta-analysis was performed using mean values of Body Mass Index (BMI) and standard deviations. The results did not show significant differences between FTO genotypes and BMI values (-0.32, 95% CI -0.45 to -0.19, I2 = 0%, p = 0.52). However, 59% of the studies identified some influence on body composition, obesity, or comorbidities. Few publications verify FTO polymorphism effects on specific groups of the older population, suggesting a reduction in the influence of this gene on the BMI with advancing age. However, we believe that more controlled studies in older populations should be performed.