Search Results (47)

Background/Objectives: The fat mass and obesity-associated (FTO) protein demethylates nuclear N6-Methyladenosine (m6A) on mRNA, facilitates tumor growth, and contributes to therapeutic resistance in multiple cancer types. Recent evidence demonstrates several roles of FTO in tumorigenesis. In this study, we seek to explore the role of FTO in non-small cell lung cancer (NSCLC) tumorigenicity and its relationship with epidermal growth factor receptor (EGFR) tyrosine kinase resistance. Methods: We performed qPCR, immunoblotting, viability assays, migration assays, and ATP assays to investigate the functions of FTO in EGFR tyrosine kinase inhibitor (TKI) resistance, specifically to erlotinib, in three NSCLC cell lines harboring either wild-type or mutant EGFR. We also performed immunohistochemistry on lung tumor tissues from patients diagnosed at different stages of NSCLC. Results: Our study found an upregulation of FTO in erlotinib-resistant (ER) cell lines at both the gene and protein levels. FTO inhibition and knockdown significantly reduced cell viability of erlotinib-resistant H2170 and PC9 cells by over 30% when treated with 0.8 µM of Dac51 and about 20% when treated with siFTO. FTO inhibition also slowed down the migration of ER cells, and the effect was even more pronounced when combined with erlotinib. Furthermore, FTO was found to be overexpressed in late-stage NSCLC tumor tissues compared to early-stage tumors, and it was upregulated in patients who smoked. Conclusions: These findings suggest FTO might mediate resistance and tumor growth by augmenting cell proliferation. In addition, FTO can be a potential prognostic marker in NSCLC patients. Full article

Prolonged breastfeeding (BF), as opposed to artificial infant formula feeding (FF), has been shown to prevent the development of obesity later in life. The aim of our narrative review is to investigate the missing molecular link between postnatal protein overfeeding—often referred to as the “early protein hypothesis”—and the subsequent transcriptional and epigenetic changes that accelerate the expansion of adipocyte stem cells (ASCs) in the adipose vascular niche during postnatal white adipose tissue (WAT) development. To achieve this, we conducted a search on the Web of Science, Google Scholar, and PubMed databases from 2000 to 2025 and reviewed 750 papers. Our findings revealed that the overactivation of mechanistic target of rapamycin complex 1 (mTORC1) and S6 kinase 1 (S6K1), which inhibits wingless (Wnt) signaling due to protein overfeeding, serves as the primary pathway promoting ASC commitment and increasing preadipocyte numbers. Moreover, excessive protein intake, combined with the upregulation of the fat mass and obesity-associated gene (FTO) and a deficiency of breast milk-derived microRNAs from lactation, disrupts the proper regulation of FTO and Wnt pathway components. This disruption enhances ASC expansion in WAT while inhibiting brown adipose tissue development. While BF has been shown to have protective effects against obesity, the postnatal transcriptional and epigenetic changes induced by excessive protein intake from FF may predispose infants to early and excessive ASC commitment in WAT, thereby increasing the risk of obesity later in life. Full article

Background/Objectives: Previous studies suggest that there is a genetically determined component of fat oxidation at rest and during exercise. To date, the FTO gene has been proposed as a candidate gene to affect fat oxidation during exercise because of the association of the “at-risk” A allele with different obesity-related factors such as increased body fat, higher appetite and elevated insulin and triglyceride levels. The A allele of the FTO gene may also be linked to obesity through a reduced capacity for fat oxidation during exercise, a topic that remains largely underexplored in the current literature. The aim of this study was to analyze the association between the FTO rs9939609 polymorphism with the rate of fat oxidation during exercise and metabolic syndrome criteria in healthy participants. Methods: A total of 80 healthy participants (41 men and 39 women) underwent comprehensive assessments, including measurements of anthropometric variables, blood pressure and blood measures of fasting glucose, triglycerides, low- and high-density lipoprotein cholesterol (LDL-c and HDL-c), insulin, interleukin-6 (IL-6) and C-reactive protein (CRP) concentrations. Additionally, the Homeostatic Model Assessment (HOMA-IR) was used to evaluate insulin resistance. Peak oxygen uptake (VO_2peak) and maximal fat oxidation rate (MFO) were also measured during an incremental cycling test. FTO rs9939609 genotyping (TT, AT, AA) was performed using genomic DNA samples obtained from a buccal swab and measured with PCR. Results: There were 32 participants (40.0%) with the TT genotype; 31 (38.8%) with the AT genotype; and 17 (21.2%) with the AA genotype. Age, body characteristics, VO_2peak, blood pressure and blood variables were similar across all three genotypes. However, serum insulin concentration and HOMA-IR were associated with the FTO rs9939609 genotype with higher values in AA with respect to AT and TT participants (p < 0.050). Still, MFO was similar in TT, AT and AA participants (0.35 ± 0.13, 0.37 ± 0.11, 0.33 ± 0.11 g/min, p = 0.702). In the dominant model, there was no statistical difference between TT and A allele carriers. However, the recessive model revealed that AA participants had higher values of body mass, body mass index, blood insulin concentration and HOMA-IR than T allele carriers (p < 0.050), with no differences in MFO. Conclusions: In our sample of healthy individuals, the FTO rs9939609 polymorphism was associated with several phenotypes associated with obesity and insulin resistance, particularly under the AA vs. T allele/recessive model. However, the FTO rs9939609 polymorphism was not associated with MFO during exercise as fat oxidation was similar across genotypes. This suggests that reduced fat oxidation during exercise is unlikely to be a cause of the obesogenic influence of the FTO AA genotype. Clinically, these findings suggest that the obesogenic effects of the FTO AA genotype are unlikely driven by impaired fat oxidation during exercise. Instead, attention should focus on mechanisms like appetite regulation and energy intake. Moreover, exercise interventions may still effectively mitigate obesity risk, as AA individuals retain normal fat oxidation capacity during exercise. Full article

Background: N6-methyladenosine (m6A) is an abundant RNA epitranscriptomic modification in eukaryotes. The m6A machinery includes cellular writer, eraser and reader proteins that regulate m6A. Pteropus alecto (P. alecto) (the Australian black flying fox) and Rousettus aegyptiacus (R. aegyptiacus) (the Egyptian fruit bat) are bats associated with several viral zoonoses yet neglected in the field of m6A epigenetics studies. Objectives: This study utilises various bioinformatics and in silico tools to genetically identify, characterise and annotate the m6A machinery in P. alecto and R. aegyptiacus. Methods: A range of bioinformatic tools were deployed to comprehensively characterise all known m6A-associated proteins of P. alecto and R. aegyptiacus. Results: Phylogenetically, the m6A fat mass and obesity-associated protein (FTO) eraser placed the order Chiroptera (an order including all bat species) in a separate clade. Additionally, it showed the lowest identity matrices in P. alecto and R. aegyptiacus when compared to other mammals (74.1% and 72.8%) and Homo sapiens (84.0% and 76.1%), respectively. When compared to humans, genetic loci-based analysis of P. alecto and R. aegyptiacus showed syntenic conservation in multiple flanking genes of 8 out the 10 m6A-associated genes. Furthermore, amino acid alignment and protein tertiary structure of the two bats’ m6A machinery demonstrated conservation in the writers but not in erasers and readers, compared to humans. Conclusions: These studies provide foundational annotation and genetic characterisation of m6A machinery in two important species of bats which can be exploited to study bat–virus interactions at the interface of epitranscriptomics. Full article

Skeletal muscle development is spotlighted in mammals since it closely relates to animal health and economic benefits to the breeding industry. Researchers have successfully unveiled many regulatory factors and mechanisms involving myogenesis. However, the effect of N⁶-methyladenosine (m⁶A) modification, especially demethylase and its regulated genes, on muscle development remains to be further explored. Here, we found that the typical demethylase FTO (fat mass- and obesity-associated protein) was highly enriched in goats’ longissimus dorsi (LD) muscles. In addition, the level of m⁶A modification on transcripts was negatively regulated by FTO during the proliferation of goat skeletal muscle satellite cells (MuSCs). Moreover, a deficiency of FTO in MuSCs significantly retarded their proliferation and promoted the expression of dystrophin-associated protein 1 (DAG1). m⁶A modifications of DAG1 mRNA were efficiently altered by FTO. Intriguingly, the results of DAG1 levels and its m⁶A enrichment from FB23-2 (FTO demethylase inhibitor)-treated cells were consistent with those of the FTO knockdown, indicating that the regulation of FTO on DAG1 depended on m⁶A modification. Further experiments showed that interfering FTO improved m⁶A modification at site DAG1-122, recognized by Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and consequently stabilized DAG1 transcripts. Our study suggests that FTO promotes the proliferation of MuSCs by regulating the expression of DAG1 through m⁶A modification. This will extend our knowledge of the m⁶A-related mechanism of skeletal muscle development in animals. Full article

Introduction. The Fat Mass and Obesity-Associated (FTO) gene encodes a demethylase, which modulates RNA N6-methyladenosine (m6A) and plays a regulatory role in adipocyte differentiation and the pathogenesis of human obesity. Methods. To understand the potential role of FTO in osteoporosis (OP), we investigated five single nucleotide variations (SNVs) in intron 1 (rs8057044, rs8050136, rs9939609, rs62033406, and rs9930506) of the FTO gene, and a missense SNV i.e., rs3736228 (A1330V), located in exon 18 of the LRP5 gene, in a cohort of postmenopausal women (n = 188) from Central Europe. Genotyping was performed with an allele discrimination assay, while haplotypes were reconstructed in the population by PHASE 2.1. Results. The rs9930506 was strongly associated with OP (p < 0.0035), which was supported by Bonferroni correction (p < 0.0175), and all SNVs located in the FTO gene were more strongly associated with severe OP with fragility fractures. Among seventeen haplotypes detected for the FTO gene, two haplotypes (H1 and H9) were frequent (frequency > 10%) and distributed in three main haplotypes pairs (H1/H1, H1/H9 and H9/H9, respectively). The pathogenic pair H1/H9 was associated with a leaner phenotype, increased fracture risk, and a lower bone mineral density (BMD), and carried the heterozygous GA of rs9930506, while the protective pair H9/H9 was associated with an increased obesity risk and carried AA alleles of rs9939609. Conclusions. Concordant associations with OP, an increased fracture risk, and a lower BMD at all skeletal sites indicate that the FTO gene is a promising candidate for OP, explaining the complex relationship with obesity and offering new perspectives for the study of the epigenetic regulation of bone metabolism. Full article

Translation is one of the main gene expression steps targeted by cellular stress, commonly referred to as translational stress, which includes treatment with anticancer drugs. While translational stress blocks the translation initiation of bulk mRNAs, it nonetheless activates the translation of specific mRNAs known as short upstream open reading frames (uORFs)-mRNAs. Among these, the ATF4 mRNA encodes a transcription factor that reprograms gene expression in cells responding to various stresses. Although the stress-induced translation of the ATF4 mRNA relies on the presence of uORFs (upstream to the main ATF4 ORF), the mechanisms mediating this effect, particularly during chemoresistance, remain elusive. Here, we report that ALKBH5 (AlkB Homolog 5) and FTO (FTO: Fat mass and obesity-associated protein), the two RNA demethylating enzymes, promote the translation of ATF4 mRNA in a transformed liver cell line (Hep3B) treated with the chemotherapeutic drug sorafenib. Using the in vitro luciferase reporter translational assay, we found that depletion of both enzymes reduced the translation of the reporter ATF4 mRNA upon drug treatment. Consistently, depletion of either protein abrogates the loading of the ATF3 mRNA into translating ribosomes as assessed by polyribosome assays coupled to RT-qPCR. Collectively, these results indicate that the ALKBH5 and FTO-mediated translation of the ATF4 mRNA is regulated at its initiation step. Using in vitro methylation assays, we found that ALKBH5 is required for the inhibition of the methylation of a reporter ATF4 mRNA at a conserved adenosine (A235) site located at its uORF2, suggesting that ALKBH5-mediated translation of ATF4 mRNA involves demethylation of its A235. Preventing methylation of A235 by introducing an A/G mutation into an ATF4 mRNA reporter renders its translation insensitive to ALKBH5 depletion, supporting the role of ALKBH5 demethylation activity in translation. Finally, targeting either ALKBH5 or FTO sensitizes Hep3B to sorafenib-induced cell death, contributing to their resistance. In summary, our data show that ALKBH5 and FTO are novel factors that promote resistance to sorafenib treatment, in part by mediating the translation of ATF4 mRNA. Full article

It is the purpose of this review to compare differences in postnatal epigenetic programming at the level of DNA and RNA methylation and later obesity risk between infants receiving artificial formula feeding (FF) in contrast to natural breastfeeding (BF). FF bears the risk of aberrant epigenetic programming at the level of DNA methylation and enhances the expression of the RNA demethylase fat mass- and obesity-associated gene (FTO), pointing to further deviations in the RNA methylome. Based on a literature search through Web of Science, Google Scholar, and PubMed databases concerning the dietary and epigenetic factors influencing FTO gene and FTO protein expression and FTO activity, FTO’s impact on postnatal adipogenic programming was investigated. Accumulated translational evidence underscores that total protein intake as well as tryptophan, kynurenine, branched-chain amino acids, milk exosomal miRNAs, NADP, and NADPH are crucial regulators modifying FTO gene expression and FTO activity. Increased FTO-mTORC1-S6K1 signaling may epigenetically suppress the WNT/$\beta$-catenin pathway, enhancing adipocyte precursor cell proliferation and adipogenesis. Formula-induced FTO-dependent alterations of the N6-methyladenosine (m6A) RNA methylome may represent novel unfavorable molecular events in the postnatal development of adipogenesis and obesity, necessitating further investigations. BF provides physiological epigenetic DNA and RNA regulation, a compelling reason to rely on BF. Full article

Background: Variants in fat mass and the obesity-associated protein (FTO) gene have long been recognized as the most significant genetic predictors of body fat mass and obesity. Nevertheless, despite the overall evidence, there are conflicting reports regarding the correlation between different polymorphisms of the FTO gene and body mass index (BMI). Additionally, it is unclear whether FTO influences metabolic syndrome (MetS) through mechanisms other than BMI’s impact. In this work, we aimed to analyze the impact of the following FTO polymorphisms on the BMI as well as MetS components in a population of young adult men. Methods: The patient group consisted of 279 Polish young adult men aged 28.92 (4.28) recruited for the MAGNETIC trial. The single-nucleotide polymorphisms (SNPs), located in the first intron of the FTO gene, were genotyped, and the results were used to identify “protective” and “risk” haplotypes and diplotypes based on the literature data. Laboratory, as well as anthropometric measurements regarding MetS, were performed. Measured MetS components included those used in the definition in accordance with the current guidelines. Data regarding dietary patterns were also collected, and principal components of the dietary patterns were identified. Results: No statistically significant correlations were identified between the analyzed FTO diplotypes and BMI (p = 0.53) or other MetS components (waist circumference p = 0.55; triglycerides p = 0.72; HDL cholesterol p = 0.33; blood glucose p = 0.20; systolic blood pressure p = 0.06; diastolic blood pressure p = 0.21). Stratification by the level of physical activity or adherence to the dietary patterns also did not result in any statistically significant result. Conclusions: Some studies have shown that FTO SNPs such as rs1421085, rs1121980, rs8050136, rs9939609, and rs9930506 have an impact on the BMI or other MetS components; nevertheless, this was not replicated in this study of Polish young adult males. Full article

Genome-wide association studies (GWAS) have successfully revealed numerous susceptibility loci for obesity. The PREDATORR study (2014) shows that in Romania, 346% of adults aged 20–79 y/o are overweight, and 31.4% are obese with a high risk of cardiometabolic complications, a number that puts almost 67% of Romania’s population in the abnormal weight group. Our study aims to investigate the current status of the genetic foundation in metabolic disease associated with obesity, applied to a pilot group of patients specifically examining the impact of known polymorphisms and their haplotype of six food intake-regulating genes, namely leptin (LEP), leptin receptor (LEP-R), serotonin receptor (5HTR2A), ghrelin (GHRL), neuropeptide Y (NPY), and fat-mass and obesity-associated protein (FTO) with the following polymorphisms: LEP A-2548G, LEPR A-223G, 5HTR2A G-1439A, GHRL G-72T, NPY T-29063C, FTO A-T, and body mass index (BMI). A notable link between the LEP-2548 rs7799039 gene’s AG genotype and the risk of obesity was observed, particularly pronounced in males aged 40–49, with an approximately seven-fold increased likelihood of obesity. The 5HTR2A rs6311 AA genotype was associated with a higher BMI, which was not statistically significant. The FTO rs9939609 gene’s AA genotype emerged as a significant predictor of obesity risk. Besides these significant findings, no substantial associations were observed with the LEPR, 5HTR2A, GHRL, and NPY genes. Haplotype association analysis showed a suggestive indication of GRGMLA (rs7799039, rs1137101, rs6311, rs696217, rs16139, rs9939609 sequence) haplotype with a susceptibility effect towards obesity predisposition. Linkage disequilibrium (LD) analysis showed statistically significant associations between LEP and LEPR gene (p = 0.04), LEP and GHRL gene (p = 0.0047), and GHRL and FTO gene (p = 0.03). Our study, to the best of our knowledge, is one of the very few on the Romanian population, and aims to be a starting point for further research on the targeted interventional strategies to reduce cardiometabolic risks. Full article

Bariatric surgery (BS) is considered the most effective intervention for patients with severe obesity and is used to maintain long-term weight loss and glycemic control. The aim of this study was to analyze the effects of genotypes and haplotypes of the fat mass and obesity-associated (FTO) and melanocortin 4 receptor (MC4R) genes on total body weight loss (TBWL), post-surgery weight, and post-BMI after bariatric surgery. We retrospectively selected 101 patients from Bajio High Specialty Regional Hospital, León Guanajuato, México, who underwent Roux-en-Y gastric bypass (RYGB) to determine their body mass index (BMI), blood pressure, biochemical characteristics, and comorbidities. Post-surgery, patients were referred for registered anthropometry and blood pressure. Glucose, lipid and hepatic profiles, and insulin, leptin, and ghrelin levels were measured, and rs9939609, rs9930506, and rs1421085 FTO and rs17782313 MC4R polymorphisms were genotyped. Six (4–8) years after BS, post-surgery weight was greater in carriers of the rs9939609 and rs1421085 risk genotypes. TBWL was lower for the rs9930506 and rs1421085 risk genotypes. Insulin and HOMA-IR were greater in patients with the three FTO polymorphisms. There were significant interaction effects of the rs9930506 and rs1421085 FTO risk genotypes on weight and BMI in response to BS. No association was found with the MC4R polymorphism. The genotypes and haplotypes of the FTO gene influence post-surgery weight, TBWL, insulin levels, and HOMA-IR. Full article

Sarcopenic obesity (SO) is a combination of obesity and sarcopenia, with diagnostic criteria defined as impaired skeletal muscle function and altered body composition (e.g., increased fat mass and reduced muscle mass). The mechanism of SO is not yet perfectly understood; however, the pathogenesis includes aging and its complications, chronic inflammation, insulin resistance (IR), and hormonal changes. Genetic background is apparent in the pathogenesis of isolated obesity, which is most often polygenic and is characterized by the additive effect of various genetic factors. The genetic etiology has not been strictly established in SO. Still, many data confirm the existence of pathogenic gene variants, e.g., Fat Mass and Obesity Associated Gene (FTO), beta-2-adrenergic receptor (ADRB2) gene, melanocortin-4 receptor (MC4R) and others with obesity. The literature on the role of these genes is scarce, and their role has not yet been thoroughly established. On the other hand, the involvement of systemic inflammation due to increased adipose tissue in SO plays a significant role in its pathophysiology through the synthesis of various cytokines such as monocyte chemoattractant protein-1 (MCP-1), IL-1Ra, IL-15, adiponectin or CRP. The lack of anti-inflammatory cytokine (e.g., IL-15) can increase SO risk, but further studies are needed to evaluate the exact mechanisms of implications of various cytokines in SO individuals. This manuscript analyses various immunogenetic and non-genetic factors and summarizes the recent findings on immunogenetics potentially impacting SO development. Full article

Ferroptosis is a newly established form of regulated cell death characterized by intracellular lipid peroxidation and iron accumulation that may be a promising cancer treatment strategy. However, the function and therapeutic value of ferroptosis in oral squamous cell carcinoma (OSCC) remain inadequately understood. In the present study, we investigated the biological role of the fat mass and obesity-associated gene (FTO) in ferroptosis in the context of OSCC. We found that OSCC had greater potential for ferroptosis, and FTO is associated with ferroptosis. Furthermore, higher FTO expression sensitized OSCC cells to ferroptosis in vitro and in vivo. Mechanistically, FTO suppressed the expression of anti-ferroptotic factors, acyl-CoA synthetase long-chain family member 3 (ACSL3) and glutathione peroxidase 4 (GPX4), by demethylating the m⁶A modification on the mRNA of ACSL3 and GPX4 and decreasing their stability. Taken together, our findings revealed that FTO promotes ferroptosis through ACSL3 and GPX4 regulation. Thus, ferroptosis activation in OSCC with high FTO levels may serve as a potential therapeutic target. Full article

N6-methyladenosine (m⁶A) is the most abundant RNA modification, regulating gene expression in physiological processes. However, its effect on the osteogenic differentiation of dental follicle stem cells (DFSCs) remains unknown. Here, m⁶A demethylases, the fat mass and obesity-associated protein (FTO), and alkB homolog 5 (ALKBH5) were overexpressed in DFSCs, followed by osteogenesis assay and transcriptome sequencing to explore potential mechanisms. The overexpression of FTO or ALKBH5 inhibited the osteogenesis of DFSCs, evidenced by the fact that RUNX2 independently decreased calcium deposition and by the downregulation of the osteogenic genes OCN and OPN. MiRNA profiling revealed that miR-7974 was the top differentially regulated gene, and the overexpression of m⁶A demethylases significantly accelerated miR-7974 degradation in DFSCs. The miR-7974 inhibitor decreased the osteogenesis of DFSCs, and its mimic attenuated the inhibitory effects of FTO overexpression. Bioinformatic prediction and RNA sequencing analysis suggested that FK506-binding protein 15 (FKBP15) was the most likely target downstream of miR-7974. The overexpression of FKBP15 significantly inhibited the osteogenesis of DFSCs via the restriction of actin cytoskeleton organization. This study provided a data resource of differentially expressed miRNA and mRNA after the overexpression of m⁶A demethylases in DFSCs. We unmasked the RUNX2-independent effects of m⁶A demethylase, miR-7974, and FKBP15 on the osteogenesis of DFSCs. Moreover, the FTO/miR-7974/FKBP15 axis and its effects on actin cytoskeleton organization were identified in DFSCs. Full article

Age-related hearing loss (ARHL), also known as presbycusis, is one of the most common neurodegenerative disorders in elderly individuals and has a prevalence of approximately 70–80% among individuals aged 65 and older. As ARHL is an intricate and multifactorial disease, the exact pathogenesis of ARHL is not fully understood. There is evidence that transcriptional dysregulation mediated by epigenetic modifications is widespread in ARHL. However, the potential role of N6-methyladenosine (m6A) modification, as a crucial component of epigenetics, in ARHL progression remains unclear. In this study, we confirmed that the downregulation of m6A modification in cochlear tissues is related to ARHL and found that the expression of the m6A methylation regulators Wilms tumour suppressor-1-associated protein (WTAP), methyltransferase-like 3 (METTL3), ALKB homologous protein 5 (ALKBH5) and fat mass and obesity-associated protein (FTO) is decreased significantly at the mRNA and protein levels in ARHL mice. Then, we used methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) to identify the differentially m6A-methylated genes in the cochlear tissues of ARHL mice. A total of 3438 genes with differential m6A methylation were identified, of which 1332 genes were m6A-hypermethylated and 2106 genes were m6A-hypomethylated in the ARHL group compared to the control group according to MeRIP-seq. Further joint analysis of RNA-Seq and MeRIP-Seq data showed that 262 genes had significant differences in both mRNA expression and m6A methylation. GO and KEGG analyses indicated that 262 unique genes were enriched mainly in the PI3K-AKT signalling pathway. In conclusion, the results of this study reveal differential m6A methylation patterns in the cochlear tissues of ARHL mice, providing a theoretical basis for further study of the pathogenesis of ARHL and potential therapeutic strategies. Full article