Fat Mass And Obesity-associated Research Articles

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 < 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.

Study the Association of Fat Mass and Obesity-associated (FTO) Gene Polymorphisms (SNP rs9939609) with Biochemical Markers in Obese Iraqi Patients

     This study aimed to evaluate the association of single nucleotide polymorphisms (SNP rs-9939609) of the fat mass and obesity-associated (FTO) gene with body mass index (BMI) and some biochemical markers in obese patients. The fat and mass obesity (FTO) gene variant specific single nucleotide polymorphism (SNP rs-9939609) with the T to A missense mutation may have a powerful association with obesity. This case-control study included 106 obese patients (57 males and 49 females) and 80 healthy control (40 males and 40 females). DNA was extracted from whole blood, and then the tetra-primer amplification refractory mutation system - polymerase chain reactions (ARMS.PCR) technique was used to limit the single nucleotide gene polymorphisms (rs9939609) of the FTO gene. Lipid profile, glycated hemoglobin (HbA1C), fasting blood sugar, insulin and FTO concentrations were measured by standard methods. In this study, the A allele in the rs9939609 was at a higher frequency of 35 (33.1%) in the obese patients and at a significant p-value = 0.039 compared with control 15 (18.7%). It significantly increased in the additive model and allele frequency (p= 0.003, 0.002 respectively). The rs9939608 SNP showed a significant association with increased BMI, insulin and homeostatic model assessment-insulin resistance (HOMO-IR) with p-values of 0.001, 0.001 and 0.028 respectively. After making adjustments for age and sex, lower levels of high-density lipoprotein (HDL) were observed in the AA and TA genotypes compared to the TT genotype (p = 0.004). While, no significant differences were recorded between the rs9939608 SNP and HbA1C, total cholesterol (TC), triglyceride (TG), very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) in obese patients

&lt;i&gt;Artocarpus Communis&lt;/i&gt; Seed Regulates P53, IRS, HsD17β2, FTO, and CYP11a Genes in Polycystic Ovarian Syndrome Rats

Polycystic ovarian syndrome (PCOS) is a prevalent endocrine illness that affects 5-10% of reproductive women globally. It is a multifaceted hormonal disorder characterized by the involvement of numerous molecular mechanisms that contribute to its development. This study investigates the effect of &lt;em&gt;Artocarpus communis &lt;/em&gt;seed on the hormonal imbalance and P53, IRS, HsD17β2, FTO, and CYP11a genes expression in the ovaries of letrozole-induced polycystic ovarian syndrome rats. To induce PCOS in 30 female Wistar rats, letrozole was administered at a dosage of 1 mg/kg. For 12 days, &lt;em&gt;Artocarpus communis &lt;/em&gt;seed aqueous extract (100 and 250 mg/kg body weight) and Clomiphene citrate (1 mg/kg body weight), a standard medication, were given. ELISA assessed luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels. The levels of P53, IRS, HsD17β2, FTO, and CYP11a gene expression in the ovaries were assessed. The aqueous extract reduced LH and increased FSH levels in Letrozole-induced PCOS rats. Additionally, seed aqueous extract (250 mg/kg bw) regulated the expression of P53, type 2 17-HSD (17-HSD), fat mass and obesity-associated (FTO), 11a-hydroxylase/17,20-desmolase (CYP11a), and insulin receptor substrate (IRS) genes in the ovaries of PCOS rats. Therefore, &lt;em&gt;Artocarpus communis&lt;/em&gt; seed might have multifaceted effects on molecular pathways associated with PCOS, potentially normalizing androgen metabolism, hormonal imbalance, and ovarian function.

Identifying Potent Fat Mass and Obesity-Associated Protein Inhibitors Using Deep Learning-Based Hybrid Procedures

The fat mass and obesity-associated (FTO) protein catalyzes metal-dependent modifications of nucleic acids, namely the demethylation of methyl adenosine inside mRNA molecules. The FTO protein has been identified as a potential target for developing anticancer therapies. Identifying a suitable ligand-targeting FTO protein is crucial to developing chemotherapeutic medicines to combat obesity and cancer. Scientists worldwide have employed many methodologies to discover a potent inhibitor for the FTO protein. This study uses deep learning-based methods and molecular docking techniques to investigate the FTO protein as a target. Our strategy involves systematically screening a database of small chemical compounds. By utilizing the crystal structures of the FTO complexed with ligands, we successfully identified three small-molecule chemical compounds (ZINC000003643476, ZINC000000517415, and ZINC000001562130) as inhibitors of the FTO protein. The identification process was accomplished by employing a combination of screening techniques, specifically deep learning (DeepBindGCN) and Autodock vina, on the ZINC database. These compounds were subjected to comprehensive analysis using 100 nanoseconds of molecular dynamics and binding free energy calculations. The findings of our study indicate the identification of three candidate inhibitors that might effectively target the human fat mass and obesity protein. The results of this study have the potential to facilitate the exploration of other chemicals that can interact with FTO. Conducting biochemical studies to evaluate these compounds’ effectiveness may contribute to improving fat mass and obesity treatment strategies.

FTO Deficiency Alleviates LPS-induced Acute Lung Injury by TXNIP/NLRP3-mediated Alveolar Epithelial Cell Pyroptosis.

N6-methyladenosine (m6A) plays a role in various diseases, but it has rarely been reported in acute lung injury (ALI). The FTO (fat mass and obesity-associated) protein can regulate mRNA metabolism by removing m6A residues. The aim of this study was to examine the role and mechanism of the m6A demethylase FTO in LPS-induced ALI. Lung epithelial FTO-knockout mice and FTO-knockdown/overexpression human alveolar epithelial (A549) cell lines were constructed to evaluate the effects of FTO on ALI. Bioinformatics analysis and a series of invivo and invitro assays were used to examine the mechanism of FTO regulation. Rescue assays were conducted to examine whether the impact of FTO on ALI depended on the TXNIP/NLRP3 pathway. In LPS-induced ALI, RNA m6A modification amounts were upregulated, and FTO expression was downregulated. In vivo, lung epithelial FTO knockout alleviated alveolar structure disorder, tissue edema, and pulmonary inflammation and improved the survival of ALI mice. In vitro, FTO knockdown reduced A549 cell damage and death induced by LPS, whereas FTO overexpression exacerbated cell damage and death. Mechanistically, bioinformatics analysis revealed that TXNIP was a downstream target of FTO. FTO deficiency mitigated pyroptosis in LPS-induced ALI via the TXNIP/NLRP3 pathway. Rescue assays confirmed that the impact of FTO on the TXNIP/NLRP3 pathway was significantly reversed by the TXNIP inhibitor SRI-37330. Deficiency of FTO alleviates LPS-induced ALI via TXNIP/NLRP3 pathway-mediated alveolar epithelial cell pyroptosis, which might be a novel therapeutic strategy for combating ALI.

Study of Genetic Drifts in Some Fat Mass and Obesity Associated Gene Variatiants in Type 2 Diabetics in Some Ethinic Groups Residing in Delta State, Nigeria

Aim: Detailing and distribution of some predominant FTO genes among subjects with diabetes mellitus selected from Igbo, Ika, Ijaw and Isoko tribes of Delta state, Nigeria.&#x0D; Study Design: Case-control, observational study.&#x0D; Place and Duration of Study: Federal Medical Center, Asaba, Delta State and Safety Molecular Pathology Laboratory Enugu, Nigeria, between March 2020 and Febuary 2022.&#x0D; Methodology:100 subjects (20 diabetic and 5 non diabetic from each of the four tribes; age range; 28-74 years) Venous blood was collected for the assay of FBS, Hb1ac and molecular assay of four variants of FTO (Fat Mass and Obesity Associated) gene. Results obtained were statistically analysed.&#x0D; Result: The genotypes identified in the subjects were AA, GA, GG, AC, CC, TT, and AT.  AA (Ijaw 17, Urhobo 18, Ika 18, Igbo 19) and GG (Ijaw 17, Urhobo 18, Ika 19, Igbo 18) had highest level of occurrence in all tribes. Recombinant genotype and recessive allele had higher number of subjects as compared to the originating genotypes. Hardy- Weinberg statistics demonstrated significant genetic deviations in rs2388405(AA -0.12 x2 =0.0002, GA 0.12 x2=0.002) rs201041270(GG-0.12 x2 =0.0002, GA 2.12 x2=0.002), and rs8050136 (CC -0.34 x2 =0.001, AC 2.32, x2=0.05) proving a chance of finding new SNP in the studied population with a probability of 2.25 as seen in the odd ratio of T allele in Igbo tribe.&#x0D; Conclusion: Statistically significant genetic drifts exist in the studied population.

Fat mass and obesity-associated (FTO) gene is essential for insulin secretion and β-cell function: In vitro studies using INS-1 cells and human pancreatic islets

AimsIn this study, we investigated the role of the FTO gene in pancreatic β-cell biology and its association with type 2 diabetes (T2D). To address this issue, human pancreatic islets and rat INS-1 (832/13) cells were used to perform gene silencing, overexpression, and functional analysis of FTO expression; levels of FTO were also measured in serum samples obtained from diabetic and obese individuals. ResultsThe findings revealed that FTO expression was reduced in islets from hyperglycemic/diabetic donors compared to normal donors. This reduction correlated with decreased INS and GLUT1 expression and increased PDX1, GCK, and SNAP25 expression. Silencing of Fto in INS-1 cells impaired insulin release and mitochondrial ATP production and increased apoptosis in pro-apoptotic cytokine-treated cells. However, glucose uptake and reactive oxygen species production rates remained unaffected. Downregulation of key β-cell genes was observed following Fto-silencing, while Glut2 and Gck were unaffected. RNA-seq analysis identified several dysregulated genes involved in metal ion binding, calcium ion binding, and protein serine/threonine kinase activity. Furthermore, our findings showed that Pdx1 or Mafa-silencing did not influence FTO protein expression. Overexpression of FTO in human islets promoted insulin secretion and upregulated INS, PDX1, MAFA, and GLUT1 expression. Serum FTO levels did not significantly differ between individuals with diabetes or obesity and their healthy counterparts. ConclusionThese findings suggest that FTO plays a crucial role in β-cell survival, metabolism, and function and point to a potential therapeutic utility of FTO in T2D patients.

The Development of Multiplex PCR-RFLP of FTO Genetics Variants

Background: Major health concern throughout the whole world is the increasing rate of obesity, either in elder group or younger group of multiracial ethnics that are believed to be associated with genetic factor that plays important role in the pathogenesis of obesity. The very first gene to be associated with obesity is fat mass and obesity-associated (FTO) gene with the involvement from many single nucleotide polymorphisms (SNPs) in the first intron of FTO. Early detection of obesity-related SNPs is very crucial in the effort of reducing obesity rate which is expected to increase by 2025.This has led to the urge of developing a method to detect individual with predisposing factors towards obesity, with the hope that this method will eventually helpful in assisting healthcare authorities to rapidly detect individual who are at high risk of being obese. Multiplex PCR-RFLP is a method for rapid detection of obesity-related SNPs using gene sequence amplifying technique and optimization done using gradient PCR technique. Thus, this study was conducted to evaluate the potential of multiplex PCR-RFLP to amplify FTO genetic variants. Materials and methods: A total of 14 UniSZA students were recruited to obtain 2 ml of peripheral whole blood for DNA extraction. Single gradient PCR dan multiplex PCR were employed to determine the optimum annealing temperature for all assigned FTO SNPs as rs9939609, rs1421085 and rs17817288. The PCR products were run on 1% of agarose gel electrophoresis and visualized under UV Gel doc Image Analyzer. These PCR products were introduced to restriction enzymes for the cutting site on genetic variation namely Bfal, HpyCH4V, HpyCH4IV for rs9939609, rs1421085 and rs17817288, respectively. Next, the PCR fragments were identified on 2% agarose gel electrophoresis under UV Gel Doc Image Analyzer. Results: The optimum annealing temperature to amplify all FTO SNPs obtained through gradient PCR was 60°C. The amplification of FTO rs9939609, rs17817288 and rs1421085 regions, showed specific size product of 151 bp, 140 bp, and 131 bp respectively. In RFLP, the fragments after restriction enzyme digestion produced homozygous wild type, heterozygous and homozygous mutant type for genotype characterization based on allele cut site by specific restriction enzyme namely BfaI, HpyCG4IV and HpyCH4V, respectively. Conclusion: This study may become preliminary data on the potential of multiplex PCR-RFLP in provide rapid diagnosis to amplify multiple FTO genetic variants.

FTO-mediated m6A demethylation regulates GnRH expression in the hypothalamus via the PLCβ3/Ca2+/CAMK signalling pathway

N6-methyladenosine (m6A) plays a crucial role in the development and functional homeostasis of the central nervous system. The fat mass and obesity-associated (FTO) gene, which is highly expressed in the hypothalamus, is closely related to female pubertal development. In this study, we found that m6A methylation decreased in the hypothalamus gradually with puberty and decreased in female rats with precocious puberty. FTO expression was increased at the same time. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) showed that the m6A methylation of PLCβ3, a key enzyme of the Ca2+ signalling pathway, was decreased significantly in the hypothalamus in precocious rats. Upregulating FTO increased PLCβ3 expression and activated the Ca2+ signalling pathway, which promoted GnRH expression. Dual-luciferase reporter and MeRIP-qPCR assays confirmed that FTO regulated m6A demethylation of PLCβ3 and promoted PLCβ3 expression. Upon overexpressing FTO in the hypothalamic arcuate nucleus (ARC) in female rats, we observed advanced puberty onset. Meanwhile, PLCβ3 and GnRH expression in the hypothalamus increased significantly, and the Ca2+ signalling pathway was activated. Our study demonstrates that FTO enhances GnRH expression, which promotes puberty onset, by regulating m6A demethylation of PLCβ3 and activating the Ca2+ signalling pathway.

Elemental evaluation, nutritional analysis, GC-MS analysis and ameliorative effects of Artocarpus communis J.R.Forst. & G.Forst. seeds’ phytoconstituents on metabolic syndrome via in silico approach

The nutritional as well as beneficial effects of the Artocarpus communis seed on metabolic syndrome complications have not been studied. In this research, the aim was to investigate the nutritional composition and beneficial effects of Artocarpus communis seeds’ phytoconstituents on the p53 core, fat mass and obesity-associated (FTO) protein and cytochrome P450 CYP11A1 domains. The elements and phytochemicals in the seed were determined through atomic absorption spectroscopy assay and gas chromatography–mass spectrometry (GC-MS) analysis, respectively. Also, the compounds detected were docked to the p53 core, FTO protein and cytochrome P450 CYP11A1 domains protein. Artocarpus communis seed contains sodium (7.824 ± 0.0134 ppm), magnesium (10.187 ± 0.0239 ppm) and iron (1.924 ± 0.0017), while zinc and cadmium were undetected. Phenolics and flavonoids were the most abundant phytochemicals in the seed. Phytoconstituents, such as pentadecanoic acid, hexadecanoic acid and methyl ester, possessing different therapeutic effects were identified via GC-MS analysis. In A. communis seed, 3-methyl-4-nitro-5-(1-pyrazolyl) pyrazole and phenanthrene were able to bind more peculiarly and specifically to the p53 core, FTO protein and cytochrome P450 CYP11A1 domains. One of the important processes that were hypothesized for the recovery of metabolic syndrome in affected victims is shown by the molecular dynamics analysis, which shows that the binding of these chemicals to the targeted structure stabilized the proteins. Therefore, Artocarpus communis seeds could be a new strategy for the management of metabolic syndrome. Communicated by Ramaswamy H. Sarma

MicroRNA-192-5p downregulates Fat Mass and Obesity-associated Protein to aggravate renal ischemia/reperfusion injury

Acute kidney injury (AKI) is a common disorder without effective therapy yet. Renal ischemia/reperfusion (I/R) injury is a common cause of AKI. MicroRNA miR-192-5p has been previously reported to be upregulated in AKI models. However, its functional role in renal I/R injury is not fully understood. This study aimed to investigate the effects and the underlying mechanism of miR-192-5p in renal I/R progression. Hypoxia/reoxygenation (H/R)-induced cell injury model in HK-2 cells and I/R-induced renal injury model in mice were established in this study. Cell counting kit-8 assay was performed to determine cell viability. Quantitative real-time PCR and western blot analysis were performed to detect gene expressions. Hematoxylin-eosin and periodic acid-Schiff staining were performed to observe the histopathological changes. Enzyme-linked immunosorbent assay was performed to detect the kidney markers’ expression. In vivo and in vitro results showed that miR-192-5p was up-regulated in the I/R-induced mice model and H/R-induced cell model, and miR-192-5p overexpression exacerbated I/R-induced renal damage. Then, the downstream target of miR-192-5p was analyzed by combining the differentially expressed mRNAs and the predicted genes and confirmed using a dual-luciferase reporter assay. It was found that miR-192-5p was found to regulate fat mass and obesity-associated (FTO) protein expression by directly targeting the 3’ untranslated region of FTO mRNA. Moreover, in vivo and in vitro studies unveiled that FTO overexpression alleviated renal I/R injury and promoted HK-2 cell viability via stimulating autophagy flux. In conclusion, miR-192-5p aggravated I/R-induced renal injury by blocking autophagy flux via down-regulating FTO.

Occurrence of rs9939609 polymorphism of the fat mass and obesity-associated (FTO) gene in adult pregnant women and its relationship with gestational weight gain

Occurrence of rs9939609 polymorphism of the fat mass and obesity-associated (FTO) gene in adult pregnant women and its relationship with gestational weight gain

Influence of polymorphisms in candidate genes on carcass and meat quality traits in rabbits.

Candidate gene is a powerful approach to study gene-trait association and offers valuable information for genetic improvement using marker-assisted selection. The current work aimed to study the polymorphisms of four single nucleotide polymorphism (SNPs) at located growth hormone (GH), insulin-like growth factor-II (IGF-II), fat mass and obesity-associated (FTO), and insulin receptor substrate-1 (IRS-1) genes, and their association with the carcass, and meat quality traits in rabbits. The SNPs were genotyped using RFLP-PCR in New Zealand White and local Baladi rabbits. The results revealed that the heterozygous genotype was the most frequent in all cases, except for the FTO SNP in LB rabbits. There was a significant effect for GH genotypes on meat lightness after slaughter and hind-part weight. While, IGF-II mutation significantly affected slaughter, hot carcass, commercial carcass, and hind-part weights. The FTO SNP was associated with cooking loss and intramuscular fat weight, and the IRS-1 SNP was significantly associated with drip loss and intramuscular fat. Specific-breed effects were obtained for IGF-II SNP on cooking loss, and for the intramuscular fat. Although the results suggested that these mutations are useful candidate genes for selection, more research for detecting more variants associated with carcass and meat quality traits in rabbits are recommended.

Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin

BackgroundDiabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N6-methyladenosine (m6A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m6A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m6A modification mechanism in diabetes-associated periodontitis.MethodsPeriodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M6A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining.ResultsDiabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m6A level in total RNA. FTO knockdown increased the m6A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m6A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling.ConclusionsAGEs impaired BMSCs osteogenesis by regulating SOST in an m6A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.

Genetic variant rs9939609 in FTO is associated with body composition and obesity risk in Korean females

IntroductionThe fat mass and obesity-associated (FTO) gene is a significant locus in obesity. However, the association between FTO genetic variants and body composition has not been fully elucidated.Research design and...

Hypothalamic FTO promotes high-fat diet-induced leptin resistance in mice through increasing CX3CL1 expression

Long-term consumption of a high-fat diet (HFD) disrupts energy homeostasis and leads to weight gain. The fat mass and obesity-associated (FTO) gene has been consistently identified to be associated with HFD-induced obesity. The hypothalamus is crucial for regulating energy balance, and HFD-induced hypothalamic leptin resistance contributes to obesity. FTO, an N6-methyladenosine (m6A) RNA methylation regulator, may be a key mediator of leptin resistance. However, the exact mechanisms remain unclear. Therefore, the present study aims to investigate the association between FTO and leptin resistance. After HFD or standard diet (SD) feeding in male mice for 22 weeks, m6A-sequencing and western blotting assays were used to identify target genes and assess protein level, and molecular interaction changes. CRISPR/Cas9 gene knockout system was employed to investigate the potential function of FTO in leptin resistance and obesity. Our data showed that chemokine (C-X3-C motif) ligand 1 (CX3CL1) was a direct downstream target of FTO-mediated m6A modification. Furthermore, upregulation of FTO/CX3CL1 and suppressor of cytokine signaling 3 (SOCS3) in the hypothalamus impaired leptin-signal transducer and activator of transcription 3 signaling, resulting in leptin resistance and obesity. Compared to wild-type (WT) mice, FTO deficiency in leptin receptor-expressing neurons of the hypothalamus significantly inhibited the upregulation of CX3CL1 and SOCS3, and partially ameliorating leptin resistance under HFD conditions. Our findings reveal that FTO involved in the hypothalamic leptin resistance and provides novel insight into the function of FTO in the contribution to hypothalamic leptin resistance and obesity.