Fat Mass And Obesity-associated Research Articles

Dynamic multilayered control of m6A RNA demethylase activity

Similar to DNA and histone, RNA can also be methylated. In its most common form, a N6-methyladenosine (m6A) chemical modification is introduced into nascent messenger ribonucleic acid (mRNA) by a specialized methyltransferase complex and removed by the RNA demethylases, Fat mass and obesity-associated (FTO), and ALKBH5. The fate of m6A-marked mRNA is uniquely diverse, ranging from degradation to stabilization/translation, which has been suggested to be largely dependent on its interaction with the family of YT521-B homology (YTH) domain-containing proteins. Here, we highlight a series of control levers that impinge on the RNA demethylases. We present evidence to indicate that intermediary metabolism and various posttranslation modifications modulate the activity, stability, and the subcellular localization of FTO and ALKBH5, further dispelling the notion that m6A methylation is not a dynamic process. We also discuss how examination of these underappreciated regulatory nodes adds a more nuanced view of the role of FTO and ALKBH5 and should guide their study in cancer and nonmalignant conditions alike.

M6A demethylase FTO transcriptionally activated by SP1 improves ischemia reperfusion-triggered acute kidney injury by activating Ambra1/ULK1-mediated autophagy.

Ischemia reperfusion (I/R) was considered as one of main causes of acute kidney injury (AKI). However, the exact mechanism remains unclear. Here, this study aimed to investigate the role and mechanism of the m6A demethylase fat mass and obesity-associated (FTO) protein in I/R-induced AKI. HK-2 cells and SD rats were utilized to establish hypoxia/reoxygenation (H/R) or I/R induced AKI models. The changes of RNAs and proteins were quantified using RT-qPCR, western blot, and immunofluorescence assays, respectively. Cell proliferation and apoptosis were assessed by CCK-8 and flow cytometry. Interactions between molecules were investigated using RIP, ChIP, Co-IP, RNA pull-down, and dual luciferase reporter assays. Global m6A quantification was evaluated by kits. TUNEL and HE staining were employed for histopathological examinations. Oxidative stress-related indicators and renal function were determined using ELISA assays. The FTO expression was downregulated in H/R-induced HK-2 cells and renal tissues from I/R-induced rats. Overexpression of FTO improved the cell viability but repressed apoptosis and oxidative stress in H/R-treated HK-2 cells, as well as enhanced renal function and alleviated kidney injury in I/R rats. Notably, the FTO overexpression significantly increased autophagy-related LC3 and ULK1 levels. When autophagy was inhibited, the protective effects of FTO in AKI were diminished. Notably, Ambra1, a crucial regulator of autophagy, was repressed in H/R-induced HK-2 cells. However, the FTO overexpression restored the Ambra1 expression by reducing m6A modification of its mRNA. SP1, acting as an upstream transcription factor, directly interacts with the FTO promoter to enhance FTO expression. Knockdown of SP1 or Ambra1 suppressed the beneficial effects of FTO upregulation on autophagy and oxidative stress injury in H/R-stimulated cells. FTO, transcriptionally activated by SP1, promoted autophagy by upregulating Ambra1/ULK1 signaling, thereby inhibiting oxidative stress and kidney injury. These findings may provide some novel insights for AKI treatment.

Exploring the therapeutic mechanisms of millet in obesity through molecular docking, pharmacokinetics, and dynamic simulation.

Obesity, a prevalent global health concern, is characterized by excessive fat accumulation, which confers significant nutritional and health risks, including a shortened lifespan and diminished wellbeing. Central to the regulation of energy balance and food intake is the fat mass and obesity-associated (FTO) protein, which modulates the interplay between caloric consumption and energy expenditure. Given its pivotal role in obesity regulation, the identification of effective inhibitors targeting the FTO protein is imperative for developing therapeutic interventions. Currently available anti-obesity drugs are often plagued by undesirable side effects. In contrast, natural plant-derived bioactive compounds are gaining prominence in the pharmaceutical industry due to their efficacy and lower incidence of adverse effects. Little Millet, a traditional cereal known for its rich nutritional profile and high satiety index, was investigated in this study using molecular docking and dynamics simulation approach for its potential as an anti-obesity agent. Our research demonstrates that four bioactive compounds from Little Millet exhibit superior binding energies ranging from 7.22 to 8.83 kcal/mol, compared to the standard anti-obesity drug, orlistat, which has a binding energy of 5.96 kcal/mol. These compounds fulfilled all drug-like criteria, including the Lipinski, Ghose, Veber, Egan, and Muegge rules, and exhibited favorable profiles in terms of distribution, metabolism, and prolonged half-life without toxicity. Conversely, orlistat was associated with hepatotoxicity, a reduced half-life, and multiple violations of drug-likeness parameters, undermining its efficacy. Molecular dynamics simulations and Gibbs free energy assessments revealed that the four identified compounds maintain stable interactions with key residues in the FTO protein's active site. We propose further validation through extensive In vitro, In vivo, and clinical studies to ascertain the therapeutic potential of these compounds in combating obesity.

M6A RNA METHYLATION AS A THERAPEUTIC TARGET IN HIGH GRADE GLIOMA

Abstract AIMS High grade glioma (HGG) is a devastating brain cancer that has poor prognostic outcomes. Very recently, the field of epitranscriptome has emerged as a novel druggable target for multiple diseases, including cancers. In the present study, we sought to investigate the functional importance of N6-methyladenosine (m6A) RNA methylation in the pathogenesis and drug resistance of paediatric and adult high grade glioma. METHOD To identify the expression of key m6A effectors, RT-qPCR and immunofluorescence were undertaken in patient derived HGG cell lines, primary low passage HGG cells and human tissues. The expression of these effectors was modified using siRNA-mediated knockdown and small molecules to identify their effects on key transcription factors. The consequences of modification on the ability of the cells to form neurospheres and invade was also assessed. Developing chemotherapy-resistant cell lines is undertaking to assess the effect of m6A RNA levels on the ability of HGG cells to adapt to environmental changes. Measuring the level of m6A-modified transcripts were achieved by developing LC-MS/MS and MeRIP (methylated RNA immunoprecipitation) qPCR techniques. RESULTS We found that key m6A effectors such as methyltransferase like 3 (METTL3), Wilms tumor 1-associating protein (WTAP) and fat mass and obesity-associated (FTO) are expressed at significantly higher level in paediatric and adult HGG models than in control at both gene and protein levels. Furthermore, these effectors regulate the expression of key transcription factors in self-renewal, cell cycle regulation and tumorigenesis. siRNA-mediated depletion of m6A effectors and inhibition of METTL3 using small molecules such as STM2457 and STM3006 reduce the capacity of cells to form neurospheres and invade as well as improving the sensitivity of HGG cells to chemotherapeutic agents. CONCLUSION Our findings suggest that m6A effectors are potential pro-oncogenic factors that, if druggable, will represent an advanced avenue in HGG therapy.

Cu2O-Mediated Heterojunction Conversion from Dual Type II to Dual Z-Scheme: Its Application in Photoelectric-Colorimetric Dual-Mode Detection of Fat Mass and Obesity-Associated (FTO) Protein.

Although the construction of heterojunction has been used in photoelectrochemical (PEC) biosensors, their potential for tunable optical properties has not been deeply explored. Based on the fact that a type-II heterojunction and Z-scheme heterojunction have the same energy band structure, effective alteration of the electron transfer pathway has been achieved by introducing unique photoactive materials into the system and exploiting the interactions between the photomaterials. Based on this, we reported a novel polarity-switchable dual-mode sensor for fat mass and obesity-associated (FTO) protein analysis. Specifically, the MgIn2S4/Bi2MoO6/Bi2S3 dual type-II heterojunction was used as the sensing interface in concert with the rolling circle amplification, CRISPR/Cas12, and terminal DNA transfer enzyme multiamplification strategies, and finally, Cu2O was captured at the sensing interface. Due to the matched energy band, the introduction of Cu2O effectively changed the electron transfer pathway and realized the conversion from a dual type-II heterojunction to a dual Z-scheme heterojunction. It caused the switch of the photocurrent from the anode to the cathode. The developed PEC method showed high sensitivity and selectivity for FTO protein detection in the range of 0.0005-500 μg/L. In addition, based on the peroxidase-like activity of Cu2O to catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine by H2O2, the electrode system also achieved the colorimetric detection of FTO protein using the naked eye with the change of the color of the detection solution from colorless to blue. The detection range was from 0.05 to 500 μg/L. This work developed a photoelectrochemical-colorimetric biosensing platform with consciously designed semiconductor structures, revealing the potential of semiconductor-structured transformations in future sensing fields.

Evaluation of Fat Mass and Obesity Associated (FTO) Gene Polymorphism in Male Androgentic Aloplecia Patients

Evaluation of Fat Mass and Obesity Associated (FTO) Gene Polymorphism in Male Androgentic Aloplecia Patients

A systematic review of the anti-inflammatory and anti-fibrotic potential of human umbilical cord mesenchymal stem cells-derived exosomes in experimental models of liver regeneration.

Chronic liver injuries and their complications are leading causes of death, especially in developing countries (Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023). The available and effective treatment plans are limited, implicating the need for innovative treatment approaches (Tsuchiya et al. in Inflamm Regener, 2019;Sharma and Nagalli in Sex/Gender-Specific Medicine in the Gastrointestinal Diseases, StatPearls Publishing, 2023;Younossi et al. in Clin Gastroenterol Hepatol 21:1978-1991, 2023;). This paper aims to summarize the effects and mechanisms of hUC-MSC-exo on liver injuries and its complications; it also suggests future directions for future research. The outcomes of interest are the morphology and histology of the liver, pathology score, liver function enzyme, glucose and lipid metabolism, and the effect hUC-MSC-exo had on gene regulation regarding liver diseases. A comprehensive review of nineteen studies was conducted to assess the effectiveness of the implementation of the hUC-MSC-Exo, instilling confidence in the validity of the findings. Regarding the morphology and histology of the liver and pathology score, hUC-MSC-exo treatment resulted in improved liver morphology post-treatment, as indicated by the reduction in pathology scores. However, these observed improvements in the liver surface are not directly attributed to the hUC-MSC-Exo itself but to the overall healing processes stimulated by the treatment. In physiological outcomes, hUC-MSC-exo also improves glucose and lipid metabolism, especially in diet-induced liver injury and its complications. In gene regulation, one interesting gene in this intervention is the fat mass and obesity-associated (FTO), in which hUC-MSC-exo combined with miRNAs can suppress FTO. HUC-MSC-Exo can improve by utilizing several possible pathways, targeting pinpoints in the pathogenesis of liver disease or glucose and lipid metabolism. This study presents hUC-MSC-exo better in all outcomes of interest compared to the control or sham group. Further specification of indications of the hUC-MSC-exo method may be beneficial and essential to be analyzed in future reviews to better understand the effectiveness of each hUC-MSC-exo dose, duration, and medium.

An association between fat mass and obesity-associated (FTO) (rs9939609) and kisspeptin-1 (KISS-1) (rs4889, rs372790354) gene polymorphisms with polycystic ovary syndrome: an updated meta-analysis and power analysis.

The present meta-analysis aimed to investigate FTO rs9939609 and KISS1 rs4889, rs372790354 gene polymorphisms and its association with PCOS in Asian population. The studies included in this article were obtained by using online databases. We searched databases such as Scopus, PubMed, Embase, and Web of Science for case-control articles related to FTO and KISS1 gene polymorphism with PCOS. Metagenyo software was used to determine the 95% confidence interval (CI) and odds ratio (OR). A total of 13 articles was included in this meta-analysis for FTO (rs9939609) and KISS1 (rs4889; rs372790354) gene polymorphisms related with PCOS in the Asian population. According to the findings of this study, people with FTO rs9939609 show an association with PCOS risk in dominant model. On contradictory, KISS1 gene polymorphism specifically, rs4889 show an association with PCOS risk in allelic, recessive, and dominant models whereas rs372790354 show an association with PCOS risk in allelic and dominant models. Power analysis was performed and PPI is > 0.04. The sting analysis network for FTO and KISS1 gene estimated 12 nodes and 23 edges. The FTO rs9939609 variant exhibits an association with an increased risk of PCOS in the dominant model. KISS1 gene polymorphism, particularly rs4889, shows a significant association with PCOS risk in allelic, recessive, and dominant models. Similarly, KISS1 rs372790354 gene is associated with PCOS risk in both allelic and dominant models. Researches were focused only on the Asian population so; it is imperative to conduct further research across diverse populations.

Fine-Scale Haplotype Mapping Reveals an Association of the FTO Gene with Osteoporosis and Fracture Risk in Postmenopausal Women.

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. 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. 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. 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.

The RNA Demethylases ALKBH5 and FTO Regulate the Translation of ATF4 mRNA in Sorafenib-Treated Hepatocarcinoma Cells.

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.

Examining the association between the FTO gene and neuroticism reveals indirect effects on subjective well-being and problematic alcohol use

Associations between the fat mass and obesity-associated (FTO) gene and obesity are well-established. However, recent studies have linked FTO to addiction phenotypes and dopaminergic signaling, thus suggesting broader psychiatric implications. We explored this assumption by conducting a phenome-wide association study across 4756 genome-wide association studies, identifying 23–26 psychiatric traits associated with FTO at the multiple-corrected significance level. These traits clustered into four categories: substance use, chronotype/sleep, well-being, and neuroticism. To validate these findings, we analyzed a functionally suggestive FTO variant (rs1421085) in a separate cohort, examining its impact on (i) alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), (ii) subjective well-being based on the WHO (Ten) Well-Being Index, and (iii) neuroticism based on Schafer’s Five Factor Model or the Karolinska Scales of Personality. Our results confirmed a direct association between rs1421085 and neuroticism that was independent of age, sex, alcohol use, body mass index (BMI), and childhood adversities. Interestingly, while no direct association with alcohol intake was observed, both cross-sectional and lagged longitudinal mediation analyses uncovered indirect relationships between rs1421085 and problematic alcohol use (AUDIT-P), with increased neuroticism acting as the intermediary. Mediation analyses also supported an indirect effect of rs1421085 on lower well-being through the pathways of increased neuroticism and BMI. Our study is the first to validate a direct association between FTO and neuroticism. However, additional studies are warranted to affirm the causal pathways linking FTO to well-being and alcohol use through neuroticism.

Silencing of FTO inhibits oxidative stress to relieve neuropathic pain by m6A modification of GPR177.

Neuropathic pain (NP) is a challenging health condition owing to its complex nature and associated multiple etiologies. The occurrence of NP involves the abnormal activity of neurons mediated by oxidative stress (OS). Previous research has demonstrated that m6A methylation plays a role in the regulatory pathway of NP. This study aimed to investigate the specific molecular pathways through which m6A methylation modifiers alleviate NP. For this purpose, an NO rat model was developed via spared nerve injury (SNI), followed by quantifying the animal's pain assessment via paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The OS in SNI rats was evaluated by measuring reactive oxygen species, superoxide dismutase, and catalase (CAT) in spinal cord tissues. Moreover, quantitative-real-time polymerase chain reaction and western blot analysis were employed for detecting fat mass and obesity-associated (FTO) and GPR177 levels, while m6A levels of GPR117 were analyzed via MeRIP. The results indicated an enhanced OS with highly expressed FTO in spinal cord tissue samples, where knocking down Fto effectively relieved NP and OS in SNI rats. Mechanistic investigations revealed that Fto-mediated reduction of Grp177 m6A modification was involved in the WNT5a/TRPV1 axis-mediated OS remission of NP. Moreover, in vitro experiment results indicated that YTHDF2 was an important m6A methylated reading protein for this process. Fto silencing leads to increased m6A methylation of Grp177 through a YTHDF2-dependent mechanism, resulting in decreased Grp177 stability and ultimately reducing NP in rats by OS suppression.

Investigating the Role of Fat Mass and Obesity-Associated (FTO) Single Nucleotide Polymorphisms and Methylation in Breast Cancer.

Background Fat mass and obesity-associated (FTO) protein is an mRNA demethylase enzyme essential for active genome regulation. The FTO gene codes for a protein that is part of the methylosome complex and has a regulatory role in cancer development. Some studies have shown a relationship between FTO and cancer, where single nucleotide polymorphisms (SNPs) may have some impact on cancer risk. The present study aimed to evaluate the risk of FTO polymorphisms rs9939609, rs1477196, and rs9930506; analyze the methylation status of FTO promoters among Mexican women with breast cancer (BC); and investigate by in silico analysis the methylation status in the region near these polymorphisms. Methods A total of 157 BC patients and 137 healthy controls were genotyped for rs9939609, rs1477196, and rs9930506 FTO polymorphisms by TaqMan SNP Genotyping Assays. Promoter methylation was analyzed by sodium bisulfite and methylation-specific polymerase chain reaction (MSP) for 78 tissue samples. An in silico analysis using The Cancer Genome Atlas Program (TCGA) database was employed to investigate the methylation state in promoter and near polymorphism locations and its relation to survival. Results The AG genotype of FTO rs9930506 was associated with BC protection (P= 0.0025; adjusted OR, 0.27; 95% CI: 0.10-0.70). rs9939609 and rs1477196, according to the results of the present study, had no relation to BC. Promoter methylation status assays by MSP revealed no changes in methylation in BC or healthy tissues. Trying to know more about the methylation in promoters and near polymorphisms' relation to survival, we performed an in silico analysis. Bioinformatics analysis showed a correlation between poor survival and methylation near polymorphisms but not with methylation in the promoter region. Conclusions The AG genotype rs9930506 has a protective function against BC. Whereas high methylation near polymorphisms was related to lower survival, the hypomethylated promoter region does not impact survival.

Therapeutic effects of Artocarpus communis J.R.Forst. & G.Forst. seeds on letrozole-induced polycystic ovary syndrome wistar rats

BackgroundHerbal extracts are an effective treatment for polycystic ovarian syndrome (PCOS) and have been shown to improve insulin resistance, hyperandrogenism, sex hormones, ovulation, and PCOS symptoms. Artocarpus communis seed's potential effects on polycystic ovary syndrome (PCOS) have not been studied. PurposeThis research aims to investigate the beneficial effects of Artocarpus communis seeds on PCOS induced by letrozole in Wistar rats. MethodsTo induce PCOS, female Wistar rats weighing between 160 g to 250 g were administered letrozole (1 mg/kg) for 21 days. Subsequently, for 12 days, the rats were given the Artocarpus communis seed methanol extract, and its hexane, DCM, ethyl acetate and aqueous fractions (100 mg/kg body weight) and Clomiphene citrate (1 mg/kg body weight), a standard medication. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels were assessed using ELISA, and the expression of P53, insulin receptor substrate (IRS), type 2 17-HSD (17-HSD), fat mass and obesity-associated (FTO), and 11a-hydroxylase/17,20-desmolase (CYP11a) genes were investigated. The data were analyzed using one-way ANOVA, and a significance threshold of p < 0.05 was set for Dunnett's Multiple Comparison Test. ResultsAdministration of the methanol extract of Artocarpus communis seed and its Hexane fraction led to a decrease in LH level and an increase in FSH and estradiol levels in the PCOS-induced animals. Furthermore, methanol extract, DCM, and ethyl acetate fraction normalize the expression of P53, insulin receptor substrate (IRS), type 2 17-HSD (17-HSD), fat mass and obesity-associated (FTO), and 11a-hydroxylase/17,20-desmolase (CYP11a) genes in PCOS rats cervix. ConclusionArtocarpus communis seed exhibited ameliorative effects on polycystic ovary conditions in Wistar rats, suggesting its potential use in the management of PCOS.

New insight on antioxidants and anti-obesity properties of two seagrasses Thalassia hemprichii and Zostera marina: an integrated molecular docking simulation with in vitro study

Background The oceans are teeming with a diverse range of marine organisms that offer unique health benefits, such as seagrass which is one of many key marine products that have garnered attention for their potential therapeutic properties. However, until now there have been few successful reports of seagrass’s metabolites profile and biological activity. Therefore, this work aims to profile metabolites or chemical constituents and assess the potential antioxidants and anti-obesity effects of two seagrasses, Thalassia hemprichii and Zostera marina. Methods Once authenticated, T. hemprichii and Z. marina were extracted with two different solvents, polar (ethanol) and nonpolar (hexane). Metabolite profiling was performed using untargeted metabolomic profiling via liquid chromatography coupled to high-resolution tandem mass spectrometry method analysis, and then antioxidant and anti-obesity capabilities were assessed by molecular docking and in vitro studies on selected receptors. Results A total of 9 and 11 metabolites were observed from T. hemprichii and Z. marina and continued molecular docking. Some of the observed compounds have promising potential as inhibitors of human inducible nitric oxide synthase, reactive oxygen species (ROS) 1 kinase, human pancreatic lipase, and fat mass and obesity-associated (FTO) proteins, including luteolin, 6-hydroxy compounds luteolin O-glucoside, luteolin-O-sulphate, Thalassiolin A, Thalassiolin C, kaempferol-7,4′-dimethylether-3-O-sulfate, apigenin, and diosmetin. T. hemprichii ethanol extract (THE) EC50 value shows antioxidant capabilities via ABTS radical scavenging activity of 76.00 μg/mL, a smaller value than standard antioxidant controls (Trolox, 76.54 μg/mL) and followed by EC50 of lipase inhibition activity by THE which has the same pattern (EC50 THE &lt; EC50 Orlistat). Conclusions This concludes that the two seagrasses have promising biological activity as candidates for functional food and/or drugs in combating free radicals and obesity.

FTO rs9939609: T>A Variant and Physical Inactivity as Important Risk Factors for Class III Obesity: A Cross-Sectional Study.

The prevalence of obesity has been increasing worldwide. It has been reported that physiological and environmental factors such as diet, culture, physical activity, and genetics are the principal factors related to obesity. The fat mass and obesity-associated (FTO) gen variant (rs9939609: T>A) has been associated with class III obesity. The A variant has been correlated with anthropometric and metabolic alterations. Therefore, the purpose of this study was to analyze the association of the FTO rs9939609: T>A variant and environmental factors with clinical, anthropometric, and biochemical variables in subjects with class III obesity. The A variant frequency was higher in the class III obesity group compared with the normal weight group (44% vs. 25%, p < 0.001). Subjects with the AA genotype had a higher body mass index (BMI) than those with the AT genotype (35.46 kg/m2 (31-39.8) vs. 26.91 kg/m2 (23.7-30), p = 0.005). Women with the AA genotype showed higher waist circumferences than the AT group (101.07 cm (90.9-111.1) vs. 85.45 cm (77-93.8) p = 0.047). The FTO A variant increases the risk by 3.54 times and physical inactivity increases the risk by 6.37 times for class III obesity. Our results suggest that among the studied variables, those most related to class III obesity were the FTO risk genotype (A allele) and physical inactivity.

Assessment of the Effect of Flavonoids Biomolecules on Fat Mass and Obesity Associated (FTO) Protein as Anti-Obesity Agents: An In-Silico Study

Assessment of the Effect of Flavonoids Biomolecules on Fat Mass and Obesity Associated (FTO) Protein as Anti-Obesity Agents: An In-Silico Study

Interaction Effects of FTO and MC4R Polymorphisms on Total Body Weight Loss, Post-Surgery Weight, and Post-Body Mass Index after Bariatric Surgery.

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.

FTO attenuates the cytotoxicity of cisplatin in KGN granulosa cell-like tumour cells by regulating the Hippo/YAP1 signalling pathway.

Premature ovarian failure (POF) is a devastating condition for women under 40 years old. Chemotherapy, especially the use of cisplatin, has been demonstrated to promote the apoptosis of granulosa cells in primary and secondary follicles, leading to POF. Our previous studies demonstrated that fat mass- and obesity-associated (FTO) plays an essential role in protecting granulosa cells from cisplatin-induced cytotoxicity. Various studies have suggested that the Hippo/YAP signalling pathway plays a significant role in regulating cell apoptosis and proliferation. Additionally, YAP1 is the main downstream target of the Hippo signalling pathway and is negatively regulated by the Hippo signalling pathway. However, whether the Hippo/YAP signalling pathway is involved in the protective effect of FTO on granulosa cells has not been determined. In this study, we found that after cisplatin treatment, the apoptosis of granulosa cells increased in a concentration-dependent manner, accompanied by the downregulation of FTO and YAP1. Furthermore, overexpression of FTO decreased cisplatin-induced granulosa cell apoptosis, inhibited the Hippo/YAP kinase cascade-induced phosphorylation of YAP1, and promoted the entry of YAP1 into the nucleus. The downstream targets of YAP1 (CTGF, CYR61, and ANKRD1) were also increased. Si-RNA-mediated downregulation of FTO promoted cisplatin-induced granulosa cell apoptosis, activated the Hippo/YAP kinase cascade, and inhibited the YAP1 entry into the nucleus. These effects were completely reversed by the small molecule inhibitor of YAP1-verteporfin (VP). Taken together, these data suggested that FTO-YAP1 plays a positive role in regulating the proliferation of injured granulosa cells induced by cisplatin.

A tagging polymorphism in fat mass and obesity-associated (FTO) gene is associated with sepsis status in children.

Sepsis is one of the most common causes of death in patients admitted to intensive care units (ICUs). The development of sepsis is significantly influenced by genetic predisposition. In this study, we highlight a potential association between a variant of the fat mass and obesity-associated (FTO) gene and risk of sepsis in children and adolescents. We investigated a first-intron tagging FTO polymorphism (rs17817449) by comparing a severe condition (SC) group, comprising 598 paediatric patients (ages 0-19 years) admitted to an ICU with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ dysfunction syndrome (MODS), with a control group consisting of 616 healthy young adults. We observed a lower prevalence (p < 0.01; OR = 0.59, 95% CI = 0.39-0.87) of the FTO TT genotype in febrile and SIRS patients compared to patients with severe illness. There was a borderline trend towards a lower prevalence of the FTO TT genotype in the control group compared to the SC group (p < 0.09, OR = 0.81, 95% CI = 0.62-1.06). Our findings suggest that rs17817449, a common FTO polymorphism, may be a predictor of sepsis in paediatric patients, and that higher body weight is protective against this clinical complication.