Role Of Fat Mass Research Articles

PP01.170 The Role of Fat Mass and Obesity-Associated Gene in Non-small Cell Lung Cancer Tumorigenicity and EGFR Tyrosine Kinase Inhibitor Resistance

PP01.170 The Role of Fat Mass and Obesity-Associated Gene in Non-small Cell Lung Cancer Tumorigenicity and EGFR Tyrosine Kinase Inhibitor Resistance

Fat mass and obesity-associated protein (FTO)-induced upregulation of flotillin-2 (FLOT2) contributes to cancer aggressiveness in diffuse large B-cell lymphoma (DLBCL) via activating the PI3K/Akt/mTOR signal pathway

The role of fat mass and obesity-associated protein (FTO)-mediated N6-methyladenosine (m6A)-demethylation has been investigated in various types of cancers, but it is still unclear whether FTO participates in the progression of diffuse large B-cell lymphoma (DLBCL). Here, by conducting Real-Time qPCR and Western Blot analysis, we verified that FTO was especially enriched in the DLBCL cells (RCK-8, LY-3, DHL-6 and U2932) compared to normal WIL2S cells. Then, the overexpression and silencing vectors for FTO were delivered into the LY-3 and U2932 cells, and our functional experiments confirmed that silencing of FTO suppressed cell viability and division, and induced apoptotic cell death in the DLBCL cells, whereas FTO-overexpression exerted opposite effects. Further mechanical experiments showed that FTO demethylated m6A modifications in flotillin-2 (FLOT2) mRNA to sustain its stability for FLOT2 upregulation, and elevated FLOT2 subsequently increased the expression levels of phosphorylated PI3K (p-PI3K), p-Akt and p-mTOR to activate the tumor-initiating PI3K/Akt/mTOR signal pathway. Of note, FLOT2 also serve as an oncogene to enhance cancer malignancy in DLBCL, and the rescuing experiments showed that FTO-ablation induced suppressing effects on the malignant phenotypes in DLBCL were all abrogated by overexpressing FLOT2. Taken together, those data hinted that FTO-mediated m6A-demethylation upregulated FLOT2 to activate the downstream PI3K/Akt/mTOR signal pathway, leading to the aggressiveness of DLBCL, which potentially provided diagnostic, therapeutic and prognostic biomarkers for DLBCL.

FTO-mediated autophagy inhibition promotes non-small cell lung cancer progression by reducing the stability of SESN2 mRNA

The role of fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) demethylase, in non-small cell lung cancer (NSCLC) has recently received widespread attention. However the underlying mechanisms of FTO-mediated autophagy regulation in NSCLC progression remain elusive. In this study, we found that FTO was significantly upregulated in NSCLC, and downregulation of FTO suppressed the growth, invasion and migration of NSCLC cells by inducing autophagy. FTO knockdown resulted in elevated m6A levels in NSCLC cells. Methylated RNA immunoprecipitation sequencing showed that sestrin 2 (SESN2) was involved in m6A regulation during autophagy in NSCLC cells. Interestingly, m6A modifications in exon 9 of SESN2 regulated its stability. FTO deficiency promoted the binding of insulin-like growth factor 2 mRNA-binding protein 1 to SESN2 mRNA, enhancing its stability and elevating its protein expression. FTO inhibited autophagic flux by downregulating SESN2, thereby promoting the growth, invasion and migration of NSCLC cells. Besides, the mechanism by which FTO blocked SESN2-mediated autophagy activation was associated with the AMPK-mTOR signaling pathway. Taken together, these findings uncover an essential role of the FTO–autophagy–SESN2 axis in NSCLC progression.

FTO genotype and body mass index reduction in childhood obesity interventions: A systematic review and meta-analysis.

Numerous guidelines have called for personalized interventions to address childhood obesity. The role of fat mass and obesity-associated gene (FTO) in the risk of childhood obesity has been summarized. However, it remains unclear whether FTO could influence individual responses to obesity interventions, especially in children. To address this, we systematically reviewed 12,255 records across 10 databases/registers and included 13 lifestyle-based obesity interventions (3980 children with overweight/obesity) reporting changes in body mass index (BMI) Z-score, BMI, waist circumference, waist-to-hip ratio, and body fat percentage after interventions. These obesity-related outcomes were first compared between children carrying different FTO genotypes (rs9939609 or its proxy) and then synthesized by random-effect meta-analysis models. The results from single-group interventions showed no evidence of associations between FTO risk allele and changes in obesity-related outcomes after interventions (e.g., BMI Z-score: -0.01; 95% CI: -0.04, 0.01). The results from controlled trials showed that associations between the FTO risk allele and changes in obesity-related outcomes did not differ by intervention/control group. To conclude, the FTO risk allele might play a minor role in the response to obesity interventions among children. Future studies might pay more attention to the accumulation effect of multiple genes in the intervention process among children.

MiR-150-5p inhibits cell proliferation and metastasis by targeting FTO in osteosarcoma.

Osteosarcoma (OS), recognized as the predominant malignant tumor originating from bones, necessitates an in-depth comprehension of its intrinsic mechanisms to pinpoint novel therapeutic targets and enhance treatment methodologies. The role of fat mass and obesity-associated (FTO) in OS, particularly its correlation with malignant traits, and the fundamental mechanism, remains to be elucidated. 1. The FTO expression and survival rate in tumors were analyzed. 2. FTO in OS cell lines was quantified utilizing western blot and PCR. 3. FTO was upregulated and downregulated separately in MG63. 4. The impact of FTO on the proliferation and migration of OS cells was evaluated using CCK-8, colony formation, wound healing, and Transwell assays. 5. The expression of miR-150-5p in OS cells-derived exosomes was identified. 6. The binding of miR-150-5p to FTO was predicted by TargetScan and confirmed by luciferase reporter assay. 7. The impact of exosome miR-150-5p on the proliferation and migration of OS cells was investigated. The expression of FTO was higher in OS tissues compared to normal tissues correlating with a worse survival rate. Furthermore, the downregulation of FTO significantly impeded the growth and metastasis of OS cells. Additionally, miR-150-5p, which was downregulated in both OS cells and their derived exosomes, was found to bind to the 3'-UTR of FTO through dual luciferase experiments. Exosomal miR-150-5p was found to decrease the expression of FTO and inhibit cell viability. We identified elevated levels of FTO in OS, which may be attributed to insufficient miR-150-5p levels in both the cells and exosomes. It suggests that the dysregulation of miR-150-5p and its interaction with FTO could potentially promote the development of OS.

Pathogenesis of sarcopenia and the relationship with fat mass: descriptive review.

Age‐associated obesity and muscle atrophy (sarcopenia) are intimately connected and are reciprocally regulated by adipose tissue and skeletal muscle dysfunction. During ageing, adipose inflammation leads to the redistribution of fat to the intra‐abdominal area (visceral fat) and fatty infiltrations in skeletal muscles, resulting in decreased overall strength and functionality. Lipids and their derivatives accumulate both within and between muscle cells, inducing mitochondrial dysfunction, disturbing β‐oxidation of fatty acids, and enhancing reactive oxygen species (ROS) production, leading to lipotoxicity and insulin resistance, as well as enhanced secretion of some pro‐inflammatory cytokines. In turn, these muscle‐secreted cytokines may exacerbate adipose tissue atrophy, support chronic low‐grade inflammation, and establish a vicious cycle of local hyperlipidaemia, insulin resistance, and inflammation that spreads systemically, thus promoting the development of sarcopenic obesity (SO). We call this the metabaging cycle. Patients with SO show an increased risk of systemic insulin resistance, systemic inflammation, associated chronic diseases, and the subsequent progression to full‐blown sarcopenia and even cachexia. Meanwhile in many cardiometabolic diseases, the ostensibly protective effect of obesity in extremely elderly subjects, also known as the ‘obesity paradox’, could possibly be explained by our theory that many elderly subjects with normal body mass index might actually harbour SO to various degrees, before it progresses to full‐blown severe sarcopenia. Our review outlines current knowledge concerning the possible chain of causation between sarcopenia and obesity, proposes a solution to the obesity paradox, and the role of fat mass in ageing.

Genetic Association of FTO rs9939609 Polymorphism with Hypertension in Pakistani Population

Background: Hypertension is a medical condition that often occurs parallel to diabetes and obesity. Previously, the role of fat mass and obesity associated (FTO) gene rs9939609 polymorphism (c.46-23525T>A) with obesity has been reported while prevalence and etiological differences exist among different regions and ethnic groups. Aim: To investigate the association of FTO rs9939609 SNP with hypertension in Pakistani population. Study design: Cross-sectional study. Place and duration of study: Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan from 1st January 2019 to 31st December 2020. Methodology: One hundred and ten diagnosed hypertension patients along with 128 healthy volunteers were selected randomly. The single nucleotide polymorphism was analyzed using Amplified Refractory Mutation System-Polymerase Chain Reaction. Results: In hypertension patients, females were found to be relatively more affected and average blood pressure lies in stage 1. However, we found no significant difference in genotypic frequencies of FTO rs9939609; TT (22.6%), AA (39.6%) and AT (37.8%) and TT (17.18%), AA (39.06%), and AT (43.75%) among HT and controls, respectively. The p and OR values for risk type genotype (AA) are 0.4697 and 0.7700 (95% CI=0.3788-1.565), respectively. Subsequently, the high percentage (60.0 %) of risk genotype (AA) was found in obese-body mass index in hypertension patients. Conclusion: FTO rs9939609 single nucleotide polymorphism may not be a genetic risk factor associated with onset of hypertension directly and is linked with obesity in Pakistani patients. Keywords: FTO, Hypertension, Obesity, Pakistani patients, rs9939609

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Zhao et al. conducted a two-sample Mendelian randomization (MR) to investigate a causal relationship between body fat composition and rheumatoid arthritis (RA). Five anthropometric traits, including body mass index (BMI), body fat percentage, whole-body fat mass, whole-body fat-free mass and appendicular lean mass, were included as exposures. The study found evidence to support a putative causal role of fat mass and body fat percentage, rather than fat-free mass and appendicular lean mass, in the development of RA, which replicates and extends our previous findings on a causal association between higher BMI and an increased risk of RA (1).

THE ROLE OF FAT MASS AND OBESITY ASSOCIATED GENE (FTO) IN SATIETY AND BINGE EATING DISORDER

Obesity is a major health problem and one of the biggest predictors of the development of chronic diseases. Variations in the Fat mass and obesity associated gene (FTO) have been shown to associate strongly with obesity. Among patients with severe obesity, there is a subpopulation that presents an eating disorder known as Binge Eating Disorder. Because of its expression in the hypothalamus, FTO could be associated with modulation of satiety and, perhaps, play a role in the genesis of BED, contributing to severe obesity. A search in PubMed was carried out with the following terms: Morbid Obesity AND FTO, FTO AND Satiety Response, Binge Eating Disorder AND FTO. No restriction on the date of publication, language or type of design was applied. Sixteen articles were found. Twelve were related to FTO and grade III obesity, and three were related to FTO and satiety. Ten studies were excluded. Thus, six articles were evaluated in this review. The scarce literature limits further conclusions about the potential impact of the associations with FTO in the treatment of obesity, but all articles included in this revision show association with at least one SNP of FTO. Further studies are required to clarify these associations, especially in relation to rs9939609 (A/T), because, up to this moment, it seems to be the one variant with greatest impact on obesity in humans.

FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.

The role of Fat Mass and Obesity-associated protein (FTO) and its substrate N6-methyladenosine (m6A) in mRNA processing and adipogenesis remains largely unknown. We show that FTO expression and m6A levels are inversely correlated during adipogenesis. FTO depletion blocks differentiation and only catalytically active FTO restores adipogenesis. Transcriptome analyses in combination with m6A-seq revealed that gene expression and mRNA splicing of grouped genes are regulated by FTO. M6A is enriched in exonic regions flanking 5′- and 3′-splice sites, spatially overlapping with mRNA splicing regulatory serine/arginine-rich (SR) protein exonic splicing enhancer binding regions. Enhanced levels of m6A in response to FTO depletion promotes the RNA binding ability of SRSF2 protein, leading to increased inclusion of target exons. FTO controls exonic splicing of adipogenic regulatory factor RUNX1T1 by regulating m6A levels around splice sites and thereby modulates differentiation. These findings provide compelling evidence that FTO-dependent m6A demethylation functions as a novel regulatory mechanism of RNA processing and plays a critical role in the regulation of adipogenesis.

The role of fat mass and skeletal muscle mass in knee osteoarthritis is different for men and women: the NEO study

To investigate if the amount of fat mass (FM) or skeletal muscle mass (SMM) is more strongly associated with knee osteoarthritis (OA), in both men and women. The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45-65 years, including 5313 participants (53% female, median body mass index (BMI) 29.9 kg/m(2)). FM (kg), fat percentage, SMM (kg) and skeletal muscle (SM) percentage were estimated using bioelectrical impedance analysis (BIA). Clinical OA was defined following the ACR criteria. Structural OA was defined based on magnetic resonance imaging (MRI) in 1142 participants. Logistic regression analyses were used to examine the associations of all body composition measures with clinical and structural knee OA per standard deviation (SD), stratified by sex and adjusted for age and height. Clinical or structural OA was present in 25% and 14% of women and 12% and 13% of men, respectively. FM and fat percentage were positively associated with clinical knee OA in men and women. SMM was positively associated, while the SM percentage was negatively associated with clinical OA in both men and women. The FM/SMM ratio was positively associated with clinical OA. All determinants showed even stronger ORs for structural knee OA. In men, SMM was more strongly associated with knee OA as compared to FM whereas in women, FM was most strongly associated. Especially a high FM/SMM ratio seems to be unfavorable in knee OA. In men, SMM is most strongly associated with knee OA whereas in women FM seems to be of most importance.

AB1226 Leptin, adiponectin, resistin, visfatin serum levels and idiopathic recurrent pericarditis: A preliminary report

BackgroundIdiopathic acute recurrent pericarditis (IRAP) represents the most troublesome complication of acute pericarditis and is an autoimmune process (1). White adipose tissue produces more than 50 adipokines that participate in...

Variation in plasma leptin levels in young Iranian children with cystic fibrosis

IntroductionPoor weight gain is one of the most important mortality hazards in cystic fibrosis (CF) patients. The mechanisms that may hinder body weight regulation are not completely understood. Leptin and its role in fat mass could be related to control of weight gain in CF patients. As the previous data are conflicting, we aimed to investigate serum leptin level in Iranian CF children compared to a control group.Material and methodsForty-three CF patients aged from 3 to 120 months and 43 age-matched controls were enrolled. Patients were recruited from the outpatient clinic of the Children's Medical Center Hospital. Controls were visited in the general outpatient clinic for an annual check-up. Both groups were divided into three subgroups based on age: 3 to 12 months, 13 to 48 months, and 49 to 120 months. Body mass index (BMI) was calculated for all the participants. Serum leptin levels were measured applying a solid phase enzyme-linked immunosorbent assay (ELISA).ResultsLeptin levels and BMI values were significantly different between patients and controls (p = 0.02, p < 0.001, respectively) but only patients aged 13–48 months had significantly higher levels of leptin than age-matched controls (p = 0.016). Overall male patients’ mean leptin level was significantly higher than in female patients (p = 0.032) and male controls (p < 0.001).ConclusionsLeptin level in our patients was significantly higher than controls. It seems that leptin levels during infancy are higher than in adult patients. Further studies are required on specific genotypes, gender and age to reveal the probable correlation with BMI and leptin levels in CF patients from different ethnic groups.

Cardiometabolic comorbidities and rheumatic diseases: Focus on the role of fat mass and adipokines

Cardiometabolic comorbidities and rheumatic diseases: Focus on the role of fat mass and adipokines

Role of fat mass and adipokines in chronic kidney disease

As traditional risk factors cannot alone explain the high prevalence and incidence of cardiovascular disease in chronic kidney disease, the complex of insulin resistance, oxidative stress, and endothelial dysfunction has increasingly been studied as an important non-traditional risk factor. Recent studies show that the adipose tissue is a complex organ with pleiotropic functions far beyond the mere storage of energy. Fat tissue secretes a number of adipokines including leptin and adiponectin, as well as cytokines, such as resistin, visfatin, tumor-necrosis factor-alpha and interleukin-6. Adipokine serum levels are markedly elevated in chronic kidney disease, likely due to a decreased renal excretion. Evidence suggests that these pluripotent signaling molecules may have multiple effects modulating insulin signaling, endothelial health and vascular outcome. Fat tissue is a storage depot for energy and a source of circulating signaling molecules. It plays an important role in the catabolic uremic milieu, and has been linked to systemic inflammation and uremic anorexia. Further research is needed to investigate the complex interactions between adipokine signaling networks and its effects on vascular health and outcome in chronic kidney disease.

Intrauterine growth retardation and puberty in girls.

Some, albeit not all studies on the relationship between intrauterine growth retardation (IUGR) and female pubertal development have found an earlier and rapidly progressing puberty as well as concomitant disorders of related functional systems such as polycystic ovary syndrome and short stature. These pubertal changes are part of a growing list of IUGR-related diseases, which includes non-insulin dependent diabetes mellitus and coronary heart disease. A pulsatile release of gonadotropin releasing hormone is thought to be a conditio-sinne-qua-non for the initiation of puberty. In the absence of prospective studies on gonadotropin releasing hormone pulse patterns in IUGR-children other markers of pubertal development such as age at menarche have been deployed. From these studies it is not clear, however, whether the findings of an earlier onset of puberty in IUGR-girls merely reflect a more rapid progression of puberty. Both the role for IUGR and the mechanisms behind the onset of puberty are still elusive. Assuming a connection between IUGR and pubertal development, parallels can be drawn between hypotheses on the longterm consequences of IUGR and hypotheses on the initiation of puberty. For example, the somatometer concept proposes a role for fat mass in the initiation of puberty, which is compatible with the hypothesis on non-skeletal catch-up growth after IUGR. The debate on the origins of puberty and the role of IUGR mainly focuses on nature and nurture. Judgmentally, studies in mono- and dizygotic twins discordant for birth weight may be of particular help.

Intrauterine Growth Retardation and Puberty in Girls

AbstractSome, albeit not all studies on the relationship between intrauterine growth retardation (IUGR) and female pubertal development have found an earlier and rapidly progressing puberty as well as concomitant disorders of related functional systems such as polycystic ovary syndrome and short stature. These pubertal changes are part of a growing list of IUGR-related diseases, which includes non-insulin dependent diabetes mellitus and coronary heart disease. A pulsatile release of gonadotropin releasing hormone is thought to be a conditio-sinne-qua-non for the initiation of puberty. In the absence of prospective studies on gonadotropin releasing hormone pulse patterns in IUGR-children other markers of pubertal development such as age at menarche have been deployed. From these studies it is not clear, however, whether the findings of an earlier onset of puberty in IUGR-girls merely reflect a more rapid progression of puberty. Both the role for IUGR and the mechanisms behind the onset of puberty are still elusive. Assuming a connection between IUGR and pubertal development, parallels can be drawn between hypotheses on the longterm consequences of IUGR and hypotheses on the initiation of puberty. For example, the somatometer concept proposes a role for fat mass in the initiation of puberty, which is compatible with the hypothesis on non-skeletal catch-up growth after IUGR. The debate on the origins of puberty and the role of IUGR mainly focuses on nature and nurture. Judgmentally, studies in mono- and dizygotic twins discordant for birth weight may be of particular help.

Author's Repsonse to Commentary on "Revisiting the Role of Fat Mass in the Life Extension Induced by Caloric Restriction"

DECENTLY, mutations in several genes in the nematode s worm (1) and in the drosphilla fly (2) resulted in a dra­ matie inerease in life span. These diseoveries support the eon­ eept that genes determine longevity. Are these diseoveries rele­ vant to humans? This year a published report showed that siblings of eentenarians live longer than siblings of the eente­ narian's eohort (3), supporting a major genetie eomponent for human longevity. On the other hand, the effeets of ealorie re­ strietion on the extension of maximallife span seem to suggest that the environment also plays an important role in mediating this effeet. Are the suggestions that longevity may be deter­ mined by genes as weIl as by the environment eontradieting eaeh other? We argue that they are not-rather the environment may eause a marked differenee in the expression of longevity related genes. Dur hypothesis article (4) may help us under­ stand the interaetion between the environment and genes, and may provide an insight into how modulation of gene expression may determine longevity. We suggest that the obvious eandi­ dates for genes that influenee longevity are those expressed in fat, or whose levels are ehanged with fat mass. As an example of the latter, insulin levels inerease with fat mass and, therefore, decrease in ealorie-restrieted animals. As reviewed (4), hyperin­ sulinemia is associated with diseases and early mortality in hu­ mans, whereas a mutation in the nematodes' insulin-signaling pathway is associated with extreme longevity. Thus, this is an example demonstrating environment modulation (ealorie re­ striction), gene mutation (in nematodes), and their relationship to longevity. Fat mass is increased by 2- to 5-fold in ad-libitum fed com­ pared with calorie-restrieted animals. If the plasma levels of certain fat-derived peptides chronically increase by that many folds, they should be considered as eandidates to affect longevity (just like insulin). Durhypothesis article focused on the example of leptin-a fat-derived hormone, whose expres­ sion is modulated by fat mass, and which has been shown to control the hypothalamic response to ealorie deprivation and energy expenditure. Moreover, while fat mass is increased by several fold, the plasma leptin levels change by -2 log scales in obese humans (5) and with nutrient access to ad libitum fed an­ imals (6). This chronic -100-fold increase in the expression of a gene product is similar to differences in expression designed by genetie manipulation. Thus, together with the known actions of

Commentary on "Revisiting the Role of Fat Mass in the Life Extension Induced by Caloric Restriction"

were allowed to eat ad libitum or were fed 2 grams of food per day. The ad-libitum fed obese mice ate more than ad-libitum fed normal mice and had a shorter length of life. However, the calorie-restricted obese mice had a greater maximum longevity than ad-libitum fed normal mice even though the body fat con­ tent of the calorie-restricted obese mice was more than twice that of the ad-libitum fed normal mice. Barzilai and Gupta criti­ cize this study because visceral fat was not separately mea­ sured, a flaw shared by all of the early studies. Barzilai and Gupta also feel these obese mice are a poor model because they lack a functional leptin peptide. I disagree because caloric re­ striction increased the longevity of these obese mice, and that indicates a reduction in leptin is not involved in the antiaging action of caloric restrietion. In contrast to the view of Barzilai and Gupta, I believe that the available evidence makes a strong case against reduction in body fat playing a role in the antiaging action of caloric restric­ tion. However, I strongly feel that this issue can and should be reassessed by using modem technology that permits noninva­ sive, longitudinal measures of total and specific depot fat. If such a study indicates a role for reduction of body fat, then the many endocrine and metabolie mechanisms suggested in this hypothesis article would be worth pursuing.

The Relationship between Growth Hormone Kinetics and Sarcopenia in Postmenopausal Women: The Role of Fat Mass and Leptin

The Relationship between Growth Hormone Kinetics and Sarcopenia in Postmenopausal Women: The Role of Fat Mass and Leptin