Human Obesity Gene Research Articles

Dynamic regulation of N6,2\u2032-O-dimethyladenosine (m6Am) in obesity

The prevalent m6Am mRNA cap modification was recently identified as a valid target for removal by the human obesity gene FTO along with the previously established m6A mRNA modification. However, the deposition and dynamics of m6Am in regulating obesity are unknown. Here, we investigate the liver m6A/m methylomes in mice fed on a high fat Western-diet and in ob/ob mice. We find that FTO levels are elevated in fat mice, and that genes which lost m6Am marking under obesity are overly downregulated, including the two fatty-acid-binding proteins FABP2, and FABP5. Furthermore, the cellular perturbation of FTO correspondingly affect protein levels of its targets. Notably, generally m6Am- but not m6A-methylated genes, are found to be highly enriched in metabolic processes. Finally, we deplete all m6A background via Mettl3 knockout, and unequivocally uncover the association of m6Am methylation with increased mRNA stability, translation efficiency, and higher protein expression. Together, these results strongly implicate a dynamic role for m6Am in obesity-related translation regulation.

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

Genotyping Method and Frequency of ADRB3-rs4994 Single Nucleotide Polymorphism Genotypes in Hanoi 3-5 Years Old Chidren

Genotyping Method and Frequency of ADRB3-rs4994 Single Nucleotide Polymorphism Genotypes in Hanoi 3-5 Years Old Chidren

Genetic Architecture of Human Obesity Traits in the Rhesus Macaque

Objective:While the metabolic consequences of obesity have been studied extensively in the rhesus macaque, corollary genetic studies of obesity are non-existent. Here, we assess genetic contributions to spontaneous adiposity in this species.Methods:We assessed phenotypic variation by age-class and sex for body mass index, waist-to-height ratio, waist-to-thigh ratio, and waist circumference in 583 macaques. We estimated total and sex-specific heritability for all traits, including waist-to-thigh ratio adjusted for BMI, as well as genotypic and phenotypic correlations. We also assessed functional genetic variation at BDNF, FTO, LEP, LEPR, MC4R, PCSK1, POMC, and SIM1 in 4 animals with extreme spontaneous adiposity.Results:Trait heritability in the combined sample was low-to-moderate (0.14–0.32), while sex-specific heritability was more substantial (0.20–0.67). Heritability was greater in females for all traits except BMI. All traits were robustly correlated, with genetic correlations of 0.63–0.93 indicating substantial pleiotropy. We discovered likely functional variants in the 4 macaques at all 8 human obesity genes, including 6 missense mutations in BDNF, FTO, LEP, LEPR, and PCSK1, and notably, 1 nonsense mutation in LEPR.Conclusions:We find a moderate polygenic contribution to adiposity in rhesus macaques, and mutations with potentially larger effects in multiple genes that influence obesity in humans.

A global evolutionary and metabolic analysis of human obesity gene risk variants

It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution.

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10−3), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.

Using C. elegans to dissect fat and feeding regulatory pathways

Fat regulation involves a complex interplay between feeding centers in the nervous system and the transport, storage and mobilization of fat in the periphery. Using mutagenesis and genome‐wide RNAi studies, we previously identified over 400 genes that regulate fat levels in C. elegans. These include components of neuroendocrine signaling, channels and transporters, transcription, metabolism and many genes with previously unassigned functions. Our findings highlight the shared ancestry of C. elegans and mammalian fat regulation. More importantly, this work identifies hundreds of new genes that participate in novel fat regulatory pathways. We have now undertaken the daunting task of understanding the modes of function of these fat regulatory genes within the context of intact organisms. These genes affect functions as diverse as metabolism and behavior.I will discuss our latest findings in dissecting the neural circuits that modulate feeding behavior and fat metabolism in C. elegans. These data will include roles for the C. elegans counterparts of human obesity genes as well as utility of C. elegans in identifying novel small molecule entities that modulate fat metabolism

Phosphorylation controls a dual-function polybasic nuclear localization sequence in the adapter protein SH2B1β to regulate its cellular function and distribution

An intriguing question in cell biology is what targets proteins to, and regulates their translocation between, specific cellular locations. Here we report that the polybasic nuclear localization sequence (NLS) required for nuclear entry of the adapter protein and candidate human obesity gene product SH2B1β, also localizes SH2B1β to the plasma membrane (PM), most probably via electrostatic interactions. Binding of SH2B1β to the PM also requires its dimerization domain. Phosphorylation of serine residues near this polybasic region, potentially by protein kinase C, releases SH2B1β from the PM and enhances nuclear entry. Release of SH2B1β from the PM and/or nuclear entry appear to be required for SH2B1β enhancement of nerve growth factor (NGF)-induced expression of urokinase plasminogen activator receptor gene and neurite outgrowth of PC12 cells. Taken together, our results provide strong evidence that the polybasic NLS region of SH2B1 serves the dual function of localizing SH2B1 to both the nucleus and the PM, the latter most probably through electrostatic interactions that are enhanced by SH2B1β dimerization. Cycling between the different cellular compartments is a consequence of the phosphorylation and dephosphorylation of serine residues near the NLS and is important for physiological effects of SH2B1, including NGF-induced gene expression and neurite outgrowth.

Association betweenESR1rs1884051 polymorphism and dietary total energy and plant protein intake on obesity in Korean men

ESR1 has been listed in the Human Obesity Gene Map as candidate gene associated with obesity. Thus, in this study, we investigated the effect of the ESR1 rs1884051 polymorphism on obesity-related variables, together with their modulations by dietary intake in Korean men. The obesity-related variables and dietary intake of 3,039 Korean men aged 40-59 years from KoGES database were analyzed. Body weight (P = 0.007), BMI (P = 0.003), waist-hip ratio (= 0.011), fat body mass (P = 0.010), and body fat percentage (P = 0.040) were significantly lower in subjects with the minor T allele of ESR1 rs1884051 than in subjects carrying the C allele. Moreover, the rs1884051 T allele was associated with a decreased risk of obesity prevalence (P = 0.040). Among the subjects whose total energy intake was below the median, carrier of the minor T allele of ESR1 rs1884051 had a lower BMI (P = 0.003) when compared with subjects carrying the C allele. In addition, among subjects whose plant protein intake was above the median, carrier of the minor T allele of ESR1 rs1884051 had a lower BMI (P = 0.044) compared with subjects carrying the C allele. Our findings demonstrate that there is a significant association between the ESR1 rs1884051 variant and obesity-related variables and this association can be potentially modified by dietary energy and plant protein intake.

Obesity: from animal models to human genetics to practical applications.

Although many animal models are used in genetic studies, the mouse is most common. Analysis of single-gene mutations, linkage analysis in crossbred strains, and gene targeting are the primary techniques used to associate obesity phenotypes with specific genes or alleles. The orthologous human gene can then be tested, either in linkage studies in families or in genome-wide association studies (GWAS), for effect on the phenotype. Frequent lack of concordance between mouse and human obesity genes may be due to the difference in phenotypes measured in humans (body mass index) versus mouse (fat mass or % body fat), lack of intermediate phenotypes, and the fact that identified genes account for only a small percentage of the heritability of common obesity, suggesting that many genes remain unknown. New technology allows analysis of individual genomes at a reasonable cost, making large-scale obesity genome projects in humans feasible. Such projects could identify common allelic variants that contribute to obesity and to variable individual response to obesity therapy. Currently, family history may be more predictive than genetics for risk of obesity, but individual testing could ultimately guide therapy and, in the aggregate, guide public health policy. The primary limitation to development of genotype-based diets is that successful randomized diet trials of widely ranging macronutrient content, adequately powered for finding rare Mendelian mutations, have not been performed.

Introduction to Genetics and Childhood Obesity: Relevance to Nursing Practice

The aims for this article are to provide an overview of the current state of research on genetic contributions to the development of childhood obesity and to suggest genetic-focused nursing practices to prevent childhood obesity. Genetic epidemiology of childhood obesity, modes to identifying obesity genes, types of human obesity genes, and nursing implications are discussed. The successful integration of genetics into nursing practice will provide opportunities for nurses to participate fully as major agents and collaborators in the health care revolution. Practicing nurses across the profession will need to become knowledgeable about genetics and take part in obesity prevention through genetic assessment of susceptibility and appropriate environmental interventions.

The obesity gene, TMEM18, is of ancient origin, found in majority of neuronal cells in all major brain regions and associated with obesity in severely obese children.

BackgroundTMEM18 is a hypothalamic gene that has recently been linked to obesity and BMI in genome wide association studies. However, the functional properties of TMEM18 are obscure.MethodsThe evolutionary history of TMEM18 was inferred using phylogenetic and bioinformatic methods. The gene's expression profile was investigated with real-time PCR in a panel of rat and mouse tissues and with immunohistochemistry in the mouse brain. Also, gene expression changes were analyzed in three feeding-related mouse models: food deprivation, reward and diet-induced increase in body weight. Finally, we genotyped 502 severely obese and 527 healthy Swedish children for two SNPs near TMEM18 (rs6548238 and rs756131).ResultsTMEM18 was found to be remarkably conserved and present in species that diverged from the human lineage over 1500 million years ago. The TMEM18 gene was widely expressed and detected in the majority of cells in all major brain regions, but was more abundant in neurons than other cell types. We found no significant changes in the hypothalamic and brainstem expression in the feeding-related mouse models. There was a strong association for two SNPs (rs6548238 and rs756131) of the TMEM18 locus with an increased risk for obesity (p = 0.001 and p = 0.002).ConclusionWe conclude that TMEM18 is involved in both adult and childhood obesity. It is one of the most conserved human obesity genes and it is found in the majority of all brain sites, including the hypothalamus and the brain stem, but it is not regulated in these regions in classical energy homeostatic models.

Hypothalamic-Specific Manipulation of Fto, the Ortholog of the Human Obesity Gene FTO, Affects Food Intake in Rats

Sequence variants in the first intron of FTO are strongly associated with human obesity and human carriers of the risk alleles show evidence for increased appetite and food intake. Mice globally lacking Fto display a complex phenotype characterised by both increased energy expenditure and increased food intake. The site of action of FTO on energy balance is unclear. Fasting reduces levels of Fto mRNA in the arcuate nucleus (ARC) of the hypothalamus, a site where Fto expression is particularly high. In this study, we have extended this nutritional link by demonstrating that consumption of a high fat diet (45%) results in a 2.5 fold increase in Arc Fto expression. We have further explored the role of hypothalamic Fto in the control of food intake by using stereotactic injections coupled with AAV technology to bi-directionally modulate Fto expression. An over expression of Fto protein by 2.5-fold in the ARC results in a 14% decrease in average daily food intake in the first week. In contrast, knocking down Arc Fto expression by 40% increases food intake by 16%. mRNA levels of Agrp, Pomc and Npy, ARC-expressed genes classically associated with the control of food intake, were not affected by the manipulation of Fto expression. However, over expression of Fto resulted in a 4-fold increase in the mRNA levels of Stat3, a signalling molecule critical for leptin receptor signalling, suggesting a possible candidate for the mediation of Fto's actions. These data provide further support for the notion that FTO itself can influence key components of energy balance, and is therefore a strong candidate for the mediation of the robust association between FTO intronic variants and adiposity. Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man.

Further support for linkage of extreme obesity to the obese gene in a study group of obese children and adolescents.

The role of the obese gene in human obesity is presently unclear. Evidence for linkage of markers flanking the gene to obesity has been found in some but not all studies. We investigated transmission disequilibrium between two highly polymorphic microsatellite markers (D7S504 and D7S1875) flanking the human obese gene (OB) and extreme obesity in a study group of German children and adolescents. Due to the early onset and severity of obesity in the ob/ob mouse we hypothesized that especially children and adolescents with extreme obesity are enriched for possible mutations in the human OB. The analysis of 88 trios (index probands and both parents) for transmission disequilibrium of a haplotype which has previously been determined to be linked to extreme obesity (Reed et al., 1996) revealed a one-sided transmission disequilibrium test (TDT) p-value of 0.039. Post hoc analyses revealed one-sided TDT p-values of 0.015 for the 214 bp allele of D7S1875 (corrected p-value = 0.03) and 0.215 for the 145 bp allele of D7S504 (corrected p-value = 0.43). These findings substantiate the evidence for linkage of extreme obesity to OB.

Genetic factors in human obesity

This paper was commissioned by the Foresight programme of the Office of Science and Innovation, Department of Trade and Industry © 2007 Queen’s Printer and Controller of HMSO; published with permission Journal compilation © 2007 The International Association for the Study of Obesity. obesity reviews 8 (Suppl. 1) , 37–40 37 obesity reviews (2007) 8 (Suppl. 1) , 37–40 OnlineOpen: This article is available free online at www.blackwell-synergy.com Blackwell Publishing LtdOxford, UKOBRObesity Reviews1467-7881© 2007 Queen’s Printer and Controller of HMSO; published with permission; Journal compilation © 2007 The International Association for the Study of Obesity ? 20078 ••3740Review Article Genetic factors in human obesity I. S. Farooqi & S. O’Rahilly

Animal models of obesity

Background Obesity stems from a prolonged imbalance between the levels of energy intake and expenditure, with the resultant surplus being stored as body lipids. Our understanding of the regulation of food intake and the physiological basis of differences in energy expenditure is owed, in large part, to studies made on animals. Moreover, animal models have been a cornerstone of studies of environmental effects, such as epigenetics, responses to high-fat and low-calorie diets and the identification and development of pharmaceuticals for obesity treatment. This review provides some examples of the animal work that has been performed, and focuses on the variation in approaches that have been taken and their potential, rather than aiming to be a comprehensive summary.

Single-Strand Conformation Polymorphism Analysis by Microchip Electrophoresis for the Rapid Detection of Point Mutation in Human Obesity Gene

We describe an effective method of microchip electrophoresis (ME) based on single strand conformation poly-morphism (SSCP) analysis to rapidly detect the point mutation, Leu72Met, in a human obesity gene. The 207-bp dsDNA in the Leu72Met region, an estimate of the child obesity DNA mutant, was amplified by polymerase chain reaction (PCR) and submitted to a conventional glass microchip analysis with a sieving matrix of 1.75% poly(vinylpyrrolidone) (Mr 1 300 000), 1.0% poly(ethyleneoxide) (Mr 600 000) and 5.0% w/w glycerol. When combined with base stacking (BS) with hydroxide ions, the SSCP-ME provided rapid analysis as well as sensitive detection. The detection sensitivity was effectively enhanced in the OH- concentration range of 0.01-0.025 M NaOH. The sensitivity and speed of this ME-based SSCP methodology for the rapid detection of Leu72Met point mutations makes this an attractive method for diagnosing childhood obesity in a clinical diagnostic laboratory.

Obesity Is Associated With Family History of ESRD in Incident Dialysis Patients

Obesity is an established risk factor for chronic kidney disease and aggregates in families. The objective of this study is to examine the relationship between obesity and family history of end-stage renal disease (ESRD). Data were collected from 25,883 incident patients with ESRD in US ESRD Network 6 (Georgia, North Carolina, and South Carolina) dialysis clinics between 1995 and 2003. Family history is defined as a first- or second-degree relative with ESRD. Body mass index (BMI) at dialysis therapy initiation was classified as underweight (BMI < 18.5 kg/m2), normal (BMI, 18.5 to <25 kg/m2), overweight (BMI, 25 to < 30 kg/m2), obese (BMI, 30 to <35 kg/m2), or morbidly obese (BMI > or = 35 kg/m2). Twenty-three percent of patients reported a family history of ESRD. Of patients reporting a family history of ESRD, 5.5% were underweight, 32.5% had normal BMI, 28.0% were overweight, 17.3% were obese, and 16.7% were morbidly obese. After controlling for age, race, sex, primary cause of ESRD, history of diabetes, history of hypertension, and estimated glomerular filtration rate at dialysis therapy initiation, reported family history of ESRD was associated with being overweight (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.08 to 1.26), obese (OR, 1.25; 95% CI, 1.14 to 1.37), and morbidly obese (OR, 1.40; 95% CI, 1.27 to 1.55). Obesity at dialysis therapy initiation was associated independently with reported family history of ESRD. This finding suggests that behavioral factors, adiposity-related genes, and gene-by-BMI interaction may contribute to familial risk for ESRD. This finding also suggests that management of obesity may be even more important for patients with a family history of ESRD than for the general population.

Molecular Interactions of Leptin and Prostate Cancer

Epidemiological studies have found obesity to be a risk factor for prostate cancer. Our prior independent studies in women have reported a strong relationship between variants of OB (leptin) gene, body mass index, and age at menarche and sporadic breast cancer. The current study investigates an association between genetic variants of the human obesity gene, serum leptin levels, and body mass index in subjects with prostate carcinoma and in age- and gender-matched normal subjects. Blood samples from 69 patients with prostate cancer and 137 age-matched control subjects were collected. Serum leptin level was investigated by radioimmunoassay, and body mass index was calculated. Allele sizes were determined via standard polymerase chain reaction. Statistical analysis was performed using SPSS10.0 computer software. There was a strong association with significantly elevated serum leptin levels, high body mass index, and higher frequency of LEPR longer alleles in patients with prostate cancer than in control subjects. By contrast, a modest but not significant increase in the frequency of LEP short alleles was found in patients with prostate cancer as compared with control subjects. Analysis within groups 1 (low leptin level and low body mass index) and 2 (other) showed a significant association only in group 2, with high frequency of OB gene variants (LEPR long alleles and LEP short alleles) in patients with prostate cancer but not in control subjects. These results represent the first report of a significant association between specific leptin gene alleles, serum leptin levels, and body mass index in subjects with prostate cancer. Consistent with prior reports, we also report a significantly elevated serum leptin level in patients with prostate cancer, suggesting a strong link with obesity as an increased risk factor.

The Human Obesity Gene Map: The 2005 Update

This paper presents the 12th update of the human obesity gene map, which incorporates published results up to the end of October 2005. Evidence from single-gene mutation obesity cases, Mendelian disorders exhibiting obesity as a clinical feature, transgenic and knockout murine models relevant to obesity, quantitative trait loci (QTL) from animal cross-breeding experiments, association studies with candidate genes, and linkages from genome scans is reviewed. As of October 2005, 176 human obesity cases due to single-gene mutations in 11 different genes have been reported, 50 loci related to Mendelian syndromes relevant to human obesity have been mapped to a genomic region, and causal genes or strong candidates have been identified for most of these syndromes. There are 244 genes that, when mutated or expressed as transgenes in the mouse, result in phenotypes that affect body weight and adiposity. The number of QTLs reported from animal models currently reaches 408. The number of human obesity QTLs derived from genome scans continues to grow, and we now have 253 QTLs for obesity-related phenotypes from 61 genome-wide scans. A total of 52 genomic regions harbor QTLs supported by two or more studies. The number of studies reporting associations between DNA sequence variation in specific genes and obesity phenotypes has also increased considerably, with 426 findings of positive associations with 127 candidate genes. A promising observation is that 22 genes are each supported by at least five positive studies. The obesity gene map shows putative loci on all chromosomes except Y. The electronic version of the map with links to useful publications and relevant sites can be found at http://obesitygene.pbrc.edu.