Obesity-related Genes Research Articles

6-Paradol Acts as a Potential Anti-obesity Vanilloid from Grains of Paradise.

Grains of Paradise (GOP), the seeds of Aframomum melegueta, has anti-obesity effects. However, the mechanisms underlying the effects remain unclear. This study sets up to study the anti-obesity impact and homeostatic effects of 6-paradol, a major vanilloid found in GOP, and investigates the physiological outputs and the lipometabolism-related gene in fat and liver in high-fat-induced obese mice with a comparison with structurally similar vanilloids (6-gingerol and 6-shogaol). The vanilloids are synthesized in adequate quantities for performing animal experiments and orally administered to 6-week-old male mice over 2 weeks. This study found that 6-paradol decreased body weight gain and visceral and subcutaneous fats in 2 weeks, whereas 6-gingerol and 6-shogaol have no effect. Additionally, 6-paradol suppresses the hepatic cholesterol and triglyceride and significantly decreases the gene expression related to fatty acid synthesis, lipid transportation, and adipocyte differentiation in both liver and adipose tissue. Moreover, phosphorylation of AMP-activated protein kinase (AMPK) that greatly contributes to lipometabolism is promoted by 6-gingerol but not 6-paradol. These results suggest that 6-paradol regulates several obesity-related genes in an AMPK-independent manner. Therefore, it could be the principal active vanilloid in GOP giving it anti-obesity properties with a different mechanism.

Influence of Single Nucleotide Polymorphism of ENPP1 and ADIPOQ on Insulin Resistance and Obesity: A Case-Control Study in a Javanese Population.

Single nucleotide polymorphisms (SNPs) in obesity-related genes, such as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) and adiponectin (ADIPOQ), potentially increase the risk of insulin resistance, the most common metabolic dysregulation related to obesity. We investigated the association of ENPP1 SNP K121Q (rs1044498) with insulin resistance and ADIPOQ SNP + 267G > T (rs1501299) with circulating adiponectin levels in a case–control study involving 55 obese and 55 lean Javanese people residing in Yogyakarta, Indonesia. Allele frequency was determined by a chi squared test or Fisher’s exact test with an expected value less than 0.05. Odds ratios and 95% confidence intervals were estimated by regression logistic analysis. The presence of the Q121 allele of ENPP1 resulted in significantly higher fasting glucose, fasting insulin levels, and HOMA-IR, as compared to homozygous K121 carriers. The risk of insulin resistance was elevated in obese individuals carrying Q121 instead of homozygous K121. Adiponectin level was significantly lower in the obese group as compared to the lean group. Obese individuals carrying homozygous protective alleles (TT) of ADIPOQ tended to have lower adiponectin levels as compared to GT and GG carriers, however, we did not find statistically significant effects of the +276G > T SNP of the ADIPOQ gene on the plasma adiponectin levels or on the development of obesity.

23-OR: ADA Presidents’ Select Abstract: Genetic Architecture and Novel Genes Implicated in Youth-Onset Type 2 Diabetes

Youth-onset type 2 diabetes (T2D) has a strong genetic predisposition and is regarded as a phenotypic extreme of adult-onset T2D. In this study, we aimed to investigate the contribution of rare coding variants to the genetic basis of youth-onset T2D by analyzing whole-exome sequences of 3,005 persons with youth-onset T2D (diagnosed before 20 years of age) from the Progress in Diabetes Genetics in Youth (ProDiGY) consortium and 9,777 ancestry matched adult controls. We identified three genes with aggregate rare variant associations reaching exome-wide significance (P<2.6×10-6). In addition, we were able to identify eight genes previously linked to diabetes that were included in the top 20 (P<2.0×10-6) overlapping biologically characterized gene sets. These 11 genes were classified into three groups: 1) monogenic diabetes-related genes (HNF1A, GCK, and RFX6), 2) obesity-related genes (MC4R, ATXN2L, GHRL, and CPQ), and 3) β-cell function related genes (SLC30A8, ABCC8, PAM, and SIX3). A novel exome-wide significant gene burden association was observed for ATXN2L with odds ratio (OR) 1.26, P=1.1×10-6. For known diabetes genes, the effect sizes of gene burden analysis in youth-onset T2D were much larger than that of adult-onset T2D: examples include MC4R (OR 3.5, P=1.7×10-11 vs. OR 2.1, P=2.7×10-10 in adults) and HNF1A (OR 7.5, P=1.2×10-10 vs. OR 1.2, P=0.022). In terms of liability variance explained, both common and rare variants contributed more to youth-onset T2D than they did to adult-onset T2D (3.1-fold enrichment for common variants, 5.3-fold enrichment for rare variants). However, greater enrichment of rare variants in youth-onset T2D caused the liability variance explained by rare variants to approach 28% of that explained by common variants, in contrast to 17% for adult-onset T2D. These data paint a picture of youth-onset T2D as a disease intermediate in extremity between monogenic diabetes and T2D, in which genetic variants in both insulin secretion and insulin response pathways are implicated. Disclosure S. Kwak: None. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. E. M. Isganaitis: None. M. W. Haymond: Advisory Panel; Self; Daiichi Sankyo, Zealand Pharma A/S, Other Relationship; Self; AstraZeneca, Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. L. L. Levitsky: Consultant; Self; Eli Lilly and Company. T. I. Pollin: None. J. C. Florez: Consultant; Self; Goldfinch Bio, Inc., Other Relationship; Self; Novo Nordisk. J. Flannick: None. On behalf of the prodigy consortium: n/a. S. Srinivasan: None. L. Chen: None. J. Todd: None. E. T. Jensen: None. J. Divers: None. A. K. Mottl: Advisory Panel; Self; Bayer U. S. C. Pihoker: None. R. Gandica: None. Funding National Institutes of Health (1R01DK125490-01)

Associations between obesity-related gene expression in maternal and cord blood and newborn adiposity: findings from the Araraquara Cohort study.

Genes involved in the regulation of metabolism, adipose tissue deposition, inflammation, and the appetite-satiety axis may play an important role in fetal development, and possibly induce permanent metabolic changes and fat accumulation. In this study we investigated: (1) obesity-related gene expression in maternal and cord blood of overweight/obese and normal-weight pregnant women; (2) associations between obesity-related gene expression in maternal and cord blood; and (3) associations of gene expression in each of maternal and cord blood with newborn adiposity. Twenty-five overweight/obese and 32 normal-weight pregnant women were selected from the Araraquara Cohort Study according to their pre-pregnancy BMI. Maternal and cord blood gene expression of LEPR, STAT3, PPARG, TLR4, IL-6, IL-10, FTO, MC4R, TNF-α, and NFκB were investigated by relative real-time PCR quantification. The body composition of the newborns was assessed by air displacement plethysmography. Associations between maternal and cord blood gene expression and markers of newborn adiposity (weight, BMI, and fat mass%) were explored by linear regression models controlling for maternal age, pre-pregnancy BMI, maternal gestational weight gain, gestational age, and newborn sex. There was higher TLR4, NFκB, and TNF-a expression, and lower IL-6 expression, in overweight/obese pregnant women and their respective newborns compared with normal-weight women and their newborns (p < 0.001). Maternal PPARG gene expression was associated with both weight and fat mass % of the newborns, and cord blood IL-10 expression was associated with BMI and fat mass %, controlling for confounders. To our knowledge, this is the first study to evaluate the relationship of maternal and cord blood gene expression with adiposity markers of the newborn. Our results provide evidence for the contribution of maternal and cord blood gene expression-particularly maternal PPARG and TLR4 expression, and cord blood IL-10 expression-to newborn weight, BMI, and fat mass %.

Identification of Key Genes and Pathways for Childhood Obesity Using System Biology Approach Based on Comprehensive Gene Information

Introduction: Childhood obesity is one of the most important public health issues of the 21st century. Epidemiological studies have suggested that obesity during childhood increases the risk of developing comorbidities, such as type 2 diabetes, later in life. Childhood obesity is a complex disease whose molecular mechanisms are not completely elucidated. In this context, a system biology approach could contribute to the scientific knowledge regarding genetic factors related to childhood obesity onset. Aim: To identify molecular mechanisms involved in childhood obesity by implementing a system biology approach. Methods: Experimentally validated and computationally predicted genes related to Pediatric Obesity (C2362324) were downloaded from the DisGeNET v7.0 database. The protein-protein interaction (PPI) network was constructed using the STRING v11.0 database and analyzed using NetworkAnalyst v3.0 and Cytoscape v3.8.1. The relevance of each node for the network structure and functionality was assessed using the degree method to define hub genes. Functional and pathway enrichment analyses were performed based on Gene Ontology (GO) terms and KEGG Pathways. Results: The search on the DisGeNET database retrieved 191 childhood obesity-related genes. The PPI network of these genes showed 19 hub genes (STAT3, SIRT1, BCL2, IRS1, PPARG, SOCS3, TGFB1, HDAC4, DNMT1, ADCY3, PPARA, NEDD4L, ACACB, NR0B2, VEGFA, APOA1, GHR, CALR, and MKKS). These hub genes were involved in biological processes of lipid storage / kinase activity, regulation of fatty-acid metabolic processes, regulation of pri-miRNA transcription by RNA polymerase II, and negative regulation of small molecules and carbohydrate metabolic processes. In terms of molecular functions, repressing of transcription factors biding was found enriched. Regarding KEGG Pathways, the hub genes are involved with adipocytokine signaling, insulin resistance, longevity regulation, and cytokine signaling pathways. Conclusion: Our approach identified 19 hub genes, which are highly connected and probably have a key role in childhood obesity. Moreover, functional enrichment analyses demonstrated they are enriched in several biological processes and pathways related to the underlying molecular mechanisms of obesity. These findings provide a more comprehensive information regarding genetic and molecular factors behind childhood obesity pathogenesis. Further experimental investigation of our findings may shed light on the pathophysiology of this disease and contribute to the identification of new therapeutic targets.

PID1 promotes HCC development through regulating TME and inhibiting inflammatory factors induced apoptosis

Abstract Objective: PID1 (Phosphotyrosine interaction domain containing 1), an obesity related gene, was reported to induce insulin resistance and play a vital role in lipid metabolism in liver. However, its influence on HCC (hepatocelluar cancer) have not been full clarified. Here, we aims to investigate the mechanism of PID1 in favoring HCC development. Method: Hydrodynamic injection was applied to overexpress PID1 specifically in liver. Adaptive immunity was evaluated through flow cytometry. Lipids metabolism was determined by metabonomics. Western blotting was utilized to determine the effects of PID1 on PI3K/AKT and RAS/RAF/ERK pathway. Result: Overexpression of PID1 specifically in liver induced HCC development within 16 weeks. The frequency of CD4+ and CD8+ T cells decreased whereas the ratio of Gr1+CD11b+ cells increased in mice bearing PID1 plasmid hydrodynamic injection. Moreover, PID1 induced liver metabolism disorder, resulted in upregulation of TG, TC, NEFA, LDL-C as well as lactate levels, thereby involved in regulating TME (tumor microenvironment) and depressed adaptive immunity. Importantly, PID1 inhibited PI3K/AKT pathway, thus restrained phosphorylation of c-RAF on ser259 site induced by p-AKT and promoted phosphorylation of c-RAF on ser338 site, leading to activation of RAS/RAF/ERK pathway. Activated c-RAF targeted to mitochondria to decrease ROS level, which alleviated toxic effect of inflammatory factors and favored HCC cells survival. Conclusion: Our results demonstrated that PID1 provoked HCC development through regulating TME to depress adaptive immunity and inhibiting apoptosis induced by inflammatory factors.

Keratinocyte‐associated Protein 3 , a Novel Adiposity Gene, May Act Through the Ileum

Obesity poses a significant health burden in the United States, and investigating obesity-related genes remains an important area of research. A previous study from our lab used outbred heterogeneous stock (HS) rats to identify Keratinocyte-associated protein 3, (Krtcap3)as a candidate gene within a quantitative trait locus for adiposity. HS rats with the Wistar-Kyoto (WKY) haplotype at this locus had increased liver expression of Krtcap3, which correlated with decreased retroperitoneal fat mass (RetroFat) and decreased serum triglycerides. We developed an in vivo whole-body knock-out rat model of Krtcap3 in the inbred WKY rat using CRISPR/Cas9. Experimental wild-type (WT) and knock-out (KO) rats were placed onto a high-fat (HFD; 60% kcal fat) or low-fat diet (LFD; 10% kcal fat) at six weeks of age and were maintained on the diet for 13 weeks, with weekly measures of body weight and food intake. We hypothesized that KO rats would have increased fat mass compared to WT rats due to altered liver lipid pathways. In an initial pilot study, we found that male and female KO rats have significantly increased body weight at six weeks of age. At the end of the study, KO females—but not males—had a significantly greater fat mass compared to WT. KO females on HFD, but not LFD, had increased food consumption. We analyzed serum and liver lipids between WT and KO rats, and found no significant genotype-driven differences. This indicated that the KO did not alter liver lipid pathways, suggesting that Krtcap3 is affecting fat mass through a tissue other than liver. Previous work has shown that WKY rats exhibit increased liver Krtcap3 relative to the other HS founder strains, but expression in other tissues has not been investigated. We hypothesize that WKY rats will have a higher Krtcap3 expression compared to the other founder strains in the tissue of action of Krtcap3. We have investigated expression patterns in the following tissues in WKY, Fischer 344, and Brown Norway rats: white and brown adipose tissue, liver, heart, kidney, skeletal muscle, ileum, colon, arcuate nucleus, and nucleus accumbens. Krtcap3 expression is significantly higher only in the WKY liver and ileum. Coupled with our food intake phenotype from the pilot study, we propose that Krtcap3 may be participating in the gut-brain axis to alter food intake and influence adiposity. Future studies will evaluate expression patterns in additional inbred strains and investigate how gut hormones are altered in the KO.

Identification of Genetic Variants in 65 Obesity Related Genes in a Cohort of Portuguese Obese Individuals.

Obesity is a major public health problem, which has a strong genetic component that interplays with environmental factors. Several genes are known to be implicated in the regulation of body weight. The identification of alleles that can be associated with obesity is a key element to control this pandemic. On the basis of a Portuguese population, 65 obesity-related genes are sequenced using Next-Generation Sequencing (NGS) in 72 individuals with obesity, in order to identify variants associated with monogenic obesity and potential risk factors. A total of 429 variants are identified, 129 of which had already been associated with the phenotype. Comparing our results with the European and Global frequencies, from 1000 Genomes project, 23 potential risk variants are identified. Six new variants are discovered in heterozygous carriers: four missense (genes ALMS1-NM_015120.4:c.5552C>T; SORCS1-NM_001013031.2:c.1072A>G and NM_001013031.2: c.2491A>C; TMEM67-NM_153704.5:c.158A>G) and two synonymous (genes BBS1-NM_024649.4:c.1437C>T; TMEM67-NM_153704.5:c.2583T>C). Functional studies should be performed to validate these new findings and evaluate their penetrance and pathogenicity. Regardless of no cases of monogenic obesity being identified, this kind of investigational study is important when we are still trying to understand the aetiology and pathophysiology of obesity. This will allow the identification of rare variants associated with obesity and the study of their prevalence in specific populational groups.

Association of metabolites with obesity based on two gene variants, MC4R rs17782313 and BDNF rs6265

Previous genome-wide association analyses for obesity related genes demonstrated the association of BDNF gene variant rs6265 and MC4R gene variant rs17782313 with body mass index (BMI). However, the associated metabolite pathways are still behind the curtain. The aim of the current study is to investigate the associations of metabolic changes in obesity with MC4R gene variant rs17782313 and BDNF variant rs6265. Gas chromatography-mass spectrometry based untargeted metabolomics approach was used and 42 identified serum metabolites were selected for statistical analyses. Significant association of seven metabolites with MC4R gene variant rs17782313 based on obesity and thirty metabolites with obesity dependent BDNF variant rs6265 using additive model (adjusted p < 0.05) was observed. This study highlights the importance of alteration of fatty acid biosynthesis, probably due to high consumption of fats may cause to develop obesity. But obesity is a complex disorder and the full clarification of this complex machinery is still distant. To understand the obesity in a better way, more studies are required to identify remaining metabolites and also mechanism of these metabolic entities.

Advantages of functional analysis in comparison of different chemometric techniques for selecting obesity-related genes of adipose tissue from high-fat diet-fed mice

Introduction: Obesity is a lifestyle disease that is becoming prevalent nowadays and is associated with a surplus in energy balance related to lipid metabolism, inflammation and hypoxic condition, resulting in maladaptive adipose tissue expansion. This study used the publicly available gene dataset to identify a small subset of important genes for diagnostics or as potential targets for therapeutics.&#x0D; Methods: Chemometric analyses by principal component analysis (PCA), random forest (RF), and genetic algorithm (GA) were used to identify 50 genes that differentiate adipose samples from high-fat diet- and normal diet-fed mice. The first 30 important genes were studied for classifying the samples using six different classification techniques. Gene ontology (GO), pathway analysis, and protein-protein interaction studies on the 50 selected genes were subsequently done to identify important functional genes. Finally, gene regulatory effects by microRNA were assessed to confirm the genes’ potential as targets for new therapeutic drugs.&#x0D; Results: The genes identified by RF are best for differentiating the samples, followed by PCA, with the least predictability shown by genes chosen by GA. However, PCA identified more genes with functional importance, such as the hub genes ATP5a1 and Apoa1. ATP5a1 is the main hub gene, whereas Apoa1 is involved in cholesterol metabolism. Vapa and Npc2 are crosstalk genes that link both of these main genes and could be targeted for therapeutic drug design.&#x0D; Conclusion: The combination of different chemometric techniques and functional analysis of genes could be used to select for a small number of genes which could serve as more suitable diagnostic or therapeutic targets.

ScanBious: Survey for Obesity Genes Using PubMed Abstracts and DisGeNET.

We used automatic text-mining of PubMed abstracts of papers related to obesity, with the aim of revealing that the information used in abstracts reflects the current understanding and key concepts of this widely explored problem. We compared expert data from DisGeNET to the results of an automated MeSH (Medical Subject Heading) search, which was performed by the ScanBious web tool. The analysis provided an overview of the obesity field, highlighting major trends such as physiological conditions, age, and diet, as well as key well-studied genes, such as adiponectin and its receptor. By intersecting the DisGeNET knowledge with the ScanBious results, we deciphered four clusters of obesity-related genes. An initial set of 100+ thousand abstracts and 622 genes was reduced to 19 genes, distributed among just a few groups: heredity, inflammation, intercellular signaling, and cancer. Rapid profiling of articles could drive personalized medicine: if the disease signs of a particular person were superimposed on a general network, then it would be possible to understand which are non-specific (observed in cohorts and, therefore, most likely have known treatment solutions) and which are less investigated, and probably represent a personalized case.

Expression of obesity-related genes in human spermatozoa affects the outcomes of reproductive treatments

To study the abundance of obesity-related gene (ORG) mRNA in human spermatozoa and its association with sperm quality parameters, embryonic development, and pregnancy rates after assisted reproduction treatment (ART). Cross-sectional study of spermatozoa ORG mRNA expression, and sperm and embryonic development parameters of infertile couples attending a single ART center. University, in collaboration with a medically assisted reproduction center. One hundred six couples seeking fertility treatment and receiving ART. Expression of spermatozoa ORG mRNA was assessed by quantitative reverse transcription-polymerase chain reaction. Sperm and embryonic development parameters were measured by board-certified embryologists. Serum β-human chorionic gonadotropin levels and fetal heartbeat detection on ultrasound were used to document biochemical and clinical pregnancy, respectively. Correlations between the abundance of ORG transcripts in spermatozoa and sperm quality, embryonic development, and achievement of pregnancy. The abundance of spermatozoa FTO mRNA was positively correlated with total sperm count (r = 0.5030), fertilization rate (r = 0.4854), embryo cleavage rate (r = 0.5705), and high-quality embryo rate (r = 0.6982). The abundance of spermatozoa MC4R transcript was negatively correlated with sperm viability (r = -0.3111) and positively correlated with biochemical pregnancy (r = 0.4420). The abundance of MC4R and GNPDA2 transcripts was higher in spermatozoa of men with asthenozoospermia and teratozoospermia than in those with normozoospermia. To our knowledge, this is the first report showing that the abundance of MC4R and FTO transcripts in spermatozoa is associated with sperm and embryo quality parameters, as well as pregnancy rates. Overall, these results further support the view that male factors beyond classic sperm quality parameters, namely the abundance of ORG transcripts, also affect the outcome of ART.

Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.

Development of a Genetic Risk Score to predict the risk of overweight and obesity in European adolescents from the HELENA study

Obesity is the result of interactions between genes and environmental factors. Since monogenic etiology is only known in some obesity-related genes, a genetic risk score (GRS) could be useful to determine the genetic predisposition to obesity. Therefore, the aim of our study was to build a GRS able to predict genetic predisposition to overweight and obesity in European adolescents. A total of 1069 adolescents (51.3% female), aged 11–19 years participating in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) cross-sectional study were genotyped. The sample was divided in non-overweight (non-OW) and overweight/obesity (OW/OB). From 611 single nucleotide polymorphisms (SNP) available, a first screening of 104 SNPs univariately associated with obesity (p < 0.20) was established selecting 21 significant SNPs (p < 0.05) in the multivariate model. Unweighted GRS (uGRS) was calculated by summing the number of risk alleles and weighted GRS (wGRS) by multiplying the risk alleles to each estimated coefficient. The area under curve (AUC) was calculated in uGRS (0.723) and wGRS (0.734) using tenfold internal cross-validation. Both uGRS and wGRS were significantly associated with body mass index (BMI) (p < .001). Both GRSs could potentially be considered as useful genetic tools to evaluate individual’s predisposition to overweight/obesity in European adolescents.

Distinct Genetic Susceptibility Patterns of the Obese and Non-obese South Indian Women with Polycystic Ovary Syndrome

The researchers studied association of 92 SNPs of the metabolic and reproductive pathways genes in the obesity related cohorts of obese PCOS cases and non-obese controls, and non-obese PCOS cases and non-obese controls and observed eleven SNPs to be significantly associated (p &lt; 0.05). While eight of those SNPs, five from FTO and one each from MTCH2, DENNDIA and THADA genes, were found to be associated in the first set involving obese PCOS cases, only three SNPs (IRS2-intronic, LOC107984901-intergenic and SUMO1P1-regulatory variants) showed association in the 2nd set involving non-obese cases. The SNPs associated in the two cohorts were distinct and mutually exclusive. However, all the SNPs associated in either obese or non-obese PCOS cohorts were not only risk-prone but also broadly represented a metabolic pathway, involving mostly obesity and T2DM related genes, prompting one to surmise if the recent spurt in PCOS prevalence is not driven by changes in the lifestyles.

Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia

BackgroundObesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated.ResultsIn the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML.ConclusionsOur findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.

Distinct Genetic Susceptibility Patterns of the Obese and Nonobese South Indian Women with Polycystic Ovary Syndrome

ABSTRACT The researchers studied association of 92 SNPs of the metabolic and reproductive pathways genes in the obesity related cohorts of obese PCOS cases and non-obese controls, and non-obese PCOS cases and non-obese controls and observed eleven SNPs to be significantly associated (pd” 0.05). While eight of those SNPs, five from FTO and one each from MTCH2, DENNDIA and THADA genes, were found to be associated in the first set involving obese PCOS cases, only three SNPs (IRS2-intronic, LOC107984901-intergenic and SUMO1P1-regulatory variants) showed association in the 2nd set involving non-obese cases. The SNPs associated in the two cohorts were distinct and mutually exclusive. However, all the SNPs associated in either obese or non-obese PCOS cohorts were not only risk-prone but also broadly represented a metabolic pathway, involving mostly obesity and T2DM related genes, prompting one to surmise if the recent spurt in PCOS prevalence is not driven by changes in the lifestyles

Kisspeptin and the Genetic Obesity Interactome.

Kisspeptin (encoded by the KISS1 gene in humans) is an excitatory neuromodulatory peptide implicated in multiple homeostatic systems, including anti-oxidation, glucose homeostasis, nutrition, locomotion, etc. Therefore, in the current obesity epidemic, kisspeptin is gaining increasing interest as a research objective. To construct an updated interactome of genetic obesity, including the kisspeptin signal transduction pathway. Kisspeptin and obesity-related genes or gene products were extracted from the biomedical literature, and a network of functional associations was created. The generated network contains 101 nodes corresponding to gene/gene products with known and/or predicted interactions. In this interactome, KISS1 and KISS1R are connected directly to the luteinizing hormone receptor (LHCGR), gonadotropin-releasing hormone receptor (GNRH1), and indirectly, through the latter, to proopiomelanocortin (POMC), glucagon, leptin (LEP), and/or pro-protein convertase subtilisin/kexin-type 1 (PCSK1), all of which are critically implicated in obesity disorders. Our updated obesidome includes kisspeptin and its connections to the genetic obesity signalosome with 12 major hubs: glucagon (GCG), insulin (INS), arginine vasopressin (AVP), G protein subunit beta 1 (GNB1) and proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), gonadotropin-releasing hormone 1 (GNRH1), adrenoceptor beta 2 and 3 (ADRB2-3), glucagon-like peptide 1 receptor (GLP1R), and melanocortin 3 receptor (MC3R) genes were identified as major "hubs" for genetic obesity, providing novel insight into the body's energy homeostasis.

Bioconversion Products of Whey by Lactic Acid Bacteria Exert Anti-Adipogenic Effect.

Microbial bioconversion using lactic acid bacteria (LAB) provides several human health benefits. Although whey and whey-derived bioactive compounds can contribute to an improvement in human health, the potential anti-obesity effect of whey bioconversion by LAB has not been well studied. This study aimed to investigate whether bioconversion of whey by Pediococcus pentosaceus KI31 and Lactobacillus sakei KI36 (KI31-W and KI36-W, respectively) inhibits 3T3-L1 preadipocyte differentiation. Both KI31-W and KI36-W reduced intracellular lipid accumulation significantly, without decreasing 3T3-L1 preadipocyte proliferation. In addition, obesity-related transcription factor (peroxisome proliferator-activated receptor γ) and genes (adipocyte fatty acid-binding protein and lipoprotein lipase) were down-regulated significantly in 3T3-L1 cells in the presence of KI31-W and KI36-W. Collectively, these results suggest that bioconversion of whey by LAB exhibits anti-adipogenic activity and may be applied as a therapeutic agent for obesity.

Methylation of Hypothalamic Tsc1-mTOR Signaling in Regulation of Obesity and Obesity Resistance.

The Tsc1-mTOR signaling pathway is often related to obesity, and epigenetic modification may lead to expression changes of obesity-related gene. Therefore, we aim to investigate the methylation of the Tsc1-mTOR signaling pathway in regulation of obesity susceptibility. Wistar rats were fed a normal diet or a high-fat diet to develop animal models. Protein and mRNA expression levels of Tsc1-mTOR signaling in the hypothalamus were determined by Western blot and quantitative real-time PCR. Methylation of Tsc1 gene promoter was detected by bisulfite genomic sequence. Both mRNA and protein expression levels of Tsc1 in DIO group hypothalamus were lower; mTOR and its downstream targets S6K1, 4EBP1, and S6 protein expression levels were higher than those of the DIO-R group and the chow group. The Tsc1 gene promoter methylation rate in the hypothalamus was 92.05 ± 3.07% in the DIO group, 87.27 ± 1.91% in the DIO-R group, and 88.18% ± 3.20% in the chow group, respectively, with significantly higher levels in the DIO group. Both the expression levels of Tsc1 gene promoter methylation and Tsc1-mTOR signaling pathway in the hypothalamus of DIO rats and DIO-R rats are different. These findings may shed light on the potential mechanism for the differentiation of obesity susceptibility.