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IRX3 obesity

Apurva Srivastava, Balraj Mittal, Jai Prakash, Pranjal Srivastava, Nimisha Srivastava, Neena Srivastava
OBJECTIVES: The aim of the study was to investigate the association of 55 SNPs in 28 genes with obesity risk in a North Indian population using a multianalytical approach. METHODS: Overall, 480 subjects from the North Indian population were studied using strict inclusion/exclusion criteria. SNP Genotyping was carried out by Sequenom Mass ARRAY platform (Sequenom, San Diego, CA) and validated Taqman(®) allelic discrimination (Applied Biosystems(®) ). Statistical analyses were performed using SPSS software version 19...
September 21, 2016: American Journal of Human Biology: the Official Journal of the Human Biology Council
Kathrin Landgraf, Markus Scholz, Peter Kovacs, Wieland Kiess, Antje Körner
BACKGROUND: Genome-wide association studies have identified variants within the FTO (fat mass and obesity associated) locus as the strongest predictors of obesity amongst all obesity-associated gene loci. Recent evidence suggests that variants in FTO directly affect human adipocyte function through targeting IRX3 and IRX5 and thermogenesis regulation. AIM: We addressed the relevance of this proposed FTO-IRX pathway in adipose tissue (AT) of children. RESULTS: Expression of IRX3 was higher in adipocytes compared to SVF...
2016: PloS One
Balraj Singh, Hannah E Kinne, Ryan D Milligan, Laura J Washburn, Mark Olsen, Anthony Lucci
We have previously shown that only 0.01% cells survive a metabolic challenge involving lack of glutamine in culture medium of SUM149 triple-negative Inflammatory Breast Cancer cell line. These cells, designated as SUM149-MA for metabolic adaptability, are resistant to chemotherapeutic drugs, and they efficiently metastasize to multiple organs in nude mice. We hypothesized that obesity-related molecular networks, which normally help in cellular and organismal survival under metabolic challenges, may help in the survival of MA cells...
2016: PloS One
George Stratigopoulos, Lisa Cole Burnett, Richard Rausch, Richard Gill, David Barth Penn, Alicja A Skowronski, Charles A LeDuc, Anthony J Lanzano, Pumin Zhang, Daniel R Storm, Dieter Egli, Rudolph L Leibel
Noncoding polymorphisms in the fat mass and obesity-associated (FTO) gene represent common alleles that are strongly associated with effects on food intake and adiposity in humans. Previous studies have suggested that the obesity-risk allele rs8050136 in the first intron of FTO alters a regulatory element recognized by the transcription factor CUX1, thereby leading to decreased expression of FTO and retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L). Here, we evaluated the effects of rs8050136 and another potential CUX1 element in rs1421085 on expression of nearby genes in human induced pluripotent stem cell-derived (iPSC-derived) neurons...
May 2, 2016: Journal of Clinical Investigation
Lilian E Hunt, Boris Noyvert, Leena Bhaw-Rosun, Abdul K Sesay, Lavinia Paternoster, Ellen A Nohr, George Davey Smith, Niels Tommerup, Thorkild I A Sørensen, Greg Elgar
BACKGROUND: Association studies have identified a number of loci that contribute to an increased body mass index (BMI), the strongest of which is in the first intron of the FTO gene on human chromosome 16q12.2. However, this region is both non-coding and under strong linkage disequilibrium, making it recalcitrant to functional interpretation. Furthermore, the FTO gene is located within a complex cis-regulatory landscape defined by a topologically associated domain that includes the IRXB gene cluster, a trio of developmental regulators...
2015: Genome Medicine
John R Speakman
A cluster of single nucleotide polymorphisms (SNPs) in the first intron of the fat mass and obesity related (FTO) gene were the first common variants discovered to be associated with body mass index and body fatness. This review summarises what has been later discovered about the biology of FTO drawing together information from both human and animal studies. Subsequent work showed that the 'at risk' alleles of these SNPs are associated with greater food intake and increased hunger/lowered satiety, but are not associated with altered resting energy expenditure or low physical activity in humans...
March 2015: Current Obesity Reports
Jin-Zhong Huang, Jian Wu, Shoukui Xiang, Shiying Sheng, Ying Jiang, Zhilong Yang, Fei Hua
Alzheimer's disease (AD) is the most common form of dementia and there currently are no effective treatment strategies available. Catalpol is an iridoid glucoside, and large quantities can be isolated from the genus Rehmannia (Orobanchaceae). The present study assessed whether catalpol had any protective effects against Alzheimer's disease using a murine model. Reactive oxygen species (ROS)-associated enzymes as well as soluble Aβ40 and Aβ42 were detected using kits. Thioflavin‑S staining was performed to detect senile plaques and reverse-transcription quantitative polymerase chain reaction was used to assess iroquois homeobox protein 3 (IRX3) and obesity‑associated genes, while western blot analysis was used for β‑secretase 1 (BACE1), insulin‑degrading enzyme (IDE) and neprilysin (NEP) detection...
January 2016: Molecular Medicine Reports
Apurva Srivastava, Balraj Mittal, Jai Prakash, Pranjal Srivastava, Nimisha Srivastava, Neena Srivastava
BACKGROUND: Obesity is an increasingly important health problem worldwide as well as in developing countries like India. Recent genetic studies suggest that obesity associated FTO and IRX3 are functionally linked and many effects due to genetic variants in FTO gene act through IRX3. AIM: To evaluate the association of FTO and IRX3 genetic variants towards obesity risk. SUBJECTS AND METHODS: North Indian individuals categorised as non-obese (BMI < 30 kg/m(2)) and obese (BMI ≥ 30 kg/m(2)) were selected...
September 2016: Annals of Human Biology
Mathias Rask-Andersen, Markus Sällman Almén, Helgi B Schiöth
Single nucleotide polymorphisms (SNPs) within a genetic region including the first two introns of the gene encoding FTO have consistently been shown to be the strongest genetic factors influencing body mass index (BMI). However, this same also contains several regulatory DNA elements that affect the expression of IRX3 and IRX5, which respectively, are located approximately 500 kb and 1.2 Mbp downstream from the BMI-associated FTO locus. Through these affected regulatory elements, genetic variation at the FTO locus influences adipocyte development leading to decreased thermogenesis and increased lipid storage...
November 2015: Human Genetics
Melina Claussnitzer, Simon N Dankel, Kyoung-Han Kim, Gerald Quon, Wouter Meuleman, Christine Haugen, Viktoria Glunk, Isabel S Sousa, Jacqueline L Beaudry, Vijitha Puviindran, Nezar A Abdennur, Jannel Liu, Per-Arne Svensson, Yi-Hsiang Hsu, Daniel J Drucker, Gunnar Mellgren, Chi-Chung Hui, Hans Hauner, Manolis Kellis
BACKGROUND: Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The FTO region harbors the strongest genetic association with obesity, yet the mechanistic basis of this association remains elusive. METHODS: We examined epigenomic data, allelic activity, motif conservation, regulator expression, and gene coexpression patterns, with the aim of dissecting the regulatory circuitry and mechanistic basis of the association between the FTO region and obesity...
September 3, 2015: New England Journal of Medicine
Silke Rinkwitz, Fan-Suo Geng, Elizabeth Manning, Maximiliano Suster, Koichi Kawakami, Thomas S Becker
Single Nucleotide Polymorphisms in FTO intron 1 have been associated with obesity risk, leading to the hypothesis that FTO is the obesity-related gene. However, other studies have shown that the FTO gene is part of the regulatory domain of the neighboring IRX3 gene and that enhancers in FTO intron 1 regulate IRX3. While Irx3 activity was shown to be necessary in the hypothalamus for the metabolic function of Irx3 in mouse, no enhancers with hypothalamic activity have been demonstrated in the risk-associated region within FTO...
October 2015: Genesis: the Journal of Genetics and Development
Chao-Yung Wang, Shian-Sen Shie, I-Chang Hsieh, Ming-Lung Tsai, Ming-Shien Wen
Variations in the human fat mass and obesity-associated gene, which encodes FTO, an 2-oxoglutarate-dependent nucleic acid demethylase, are associated with increased risk of obesity. These FTO variations were recently shown to affect IRX3 and the exact function of FTO is still controversial. Obesity is closely linked to circadian rhythm. To understand the role of FTO in circadian rhythm, we analyzed the circadian rhythm of FTO deficient mice. FTO deficient mice had robust circadian locomotor activity rhythms with prolonged periods...
August 28, 2015: Biochemical and Biophysical Research Communications
Justiina Ronkainen, Tuija J Huusko, Raija Soininen, Eleonora Mondini, Francesca Cinti, Kari A Mäkelä, Miia Kovalainen, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Sylvain Sebert, Markku J Savolainen, Tuire Salonurmi
Common variants of human fat mass- and obesity-associated gene Fto have been linked with higher body mass index, but the biological explanation for the link has remained obscure. Recent findings suggest that these variants affect the homeobox protein IRX3. Here we report that FTO has a role in white adipose tissue which modifies its response to high-fat feeding. Wild type and Fto-deficient mice were exposed to standard or high-fat diet for 16 weeks after which metabolism, behavior and white adipose tissue morphology were analyzed together with adipokine levels and relative expression of genes regulating white adipose tissue adipogenesis and Irx3...
2015: Scientific Reports
Y C Loraine Tung, Giles S H Yeo, Stephen O'Rahilly, Anthony P Coll
The fat mass and obesity-associated (FTO) gene was placed center stage when common intronic variants within the gene were robustly associated with human obesity. Murine models of perturbed Fto expression have shown effects on body weight and composition. However, a clear understanding of the link between FTO intronic variants and FTO activity has remained elusive. Two recent reports now indicate that obesity-associated SNPs appear functionally connected not with FTO but with two neighboring genes: IRX3 and RPGRIP1L...
November 4, 2014: Cell Metabolism
Pawan Gulati, Edward Avezov, Marcella Ma, Robin Antrobus, Paul Lehner, Stephen O'Rahilly, Giles S H Yeo
SNPs (single nucleotide polymorphisms) on a chromosome 16 locus encompassing FTO, as well as IRX3, 5, 6, FTM and FTL are robustly associated with human obesity. FTO catalyses the Fe(II)- and 2OG-dependent demethylation of RNA and is an AA (amino acid) sensor that couples AA levels to mTORC1 (mammalian target of rapamycin complex 1) signalling, thereby playing a key role in regulating growth and translation. However, the cellular compartment in which FTO primarily resides to perform its biochemical role is unclear...
2014: Bioscience Reports
Giles S H Yeo
Genomewide association studies (GWAS) have indicated that SNPs on a chromosome 16 locus encompassing FTO, as well as IRX3, 5, 6, FTM and FTL are robustly associated with human obesity. GWAS, however, are by nature gene agnostic, and SNPs reaching the appropriate statistical threshold for a given phenotype can appear anywhere in the genome, within, near or far away from any coding sequence. Thus a major challenge in the field has been to translate these statistical hits into real biological insight. The key question is which of these genes are responsible for the association with obesity, and what is the underlying mechanism? With loss of function FTO mutations in both mice and humans resulting in severe growth retardation and mice globally over-expressing FTO being obese, the initial attention was focussed on this gene...
November 2014: Molecular and Cellular Endocrinology
Jonathan Cedernaes, Christian Benedict
No abstract text is available yet for this article.
August 2014: Molecular Metabolism
Joana Osório
No abstract text is available yet for this article.
June 2014: Nature Reviews. Endocrinology
Scott Smemo, Juan J Tena, Kyoung-Han Kim, Eric R Gamazon, Noboru J Sakabe, Carlos Gómez-Marín, Ivy Aneas, Flavia L Credidio, Débora R Sobreira, Nora F Wasserman, Ju Hee Lee, Vijitha Puviindran, Davis Tam, Michael Shen, Joe Eun Son, Niki Alizadeh Vakili, Hoon-Ki Sung, Silvia Naranjo, Rafael D Acemel, Miguel Manzanares, Andras Nagy, Nancy J Cox, Chi-Chung Hui, Jose Luis Gomez-Skarmeta, Marcelo A Nóbrega
Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes. However, no direct connection between the obesity-associated variants and FTO expression or function has been made. Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3...
March 20, 2014: Nature
Simon N Dankel, Dag J Fadnes, Anne-Kristin Stavrum, Christine Stansberg, Rita Holdhus, Tuyen Hoang, Vivian L Veum, Bjørn Jostein Christensen, Villy Våge, Jørn V Sagen, Vidar M Steen, Gunnar Mellgren
BACKGROUND: In obesity, impaired adipose tissue function may promote secondary disease through ectopic lipid accumulation and excess release of adipokines, resulting in systemic low-grade inflammation, insulin resistance and organ dysfunction. However, several of the genes regulating adipose tissue function in obesity are yet to be identified. METHODOLOGY/PRINCIPAL FINDINGS: In order to identify novel candidate genes that may regulate adipose tissue function, we analyzed global gene expression in abdominal subcutaneous adipose tissue before and one year after bariatric surgery (biliopancreatic diversion with duodenal switch, BPD/DS) (n = 16)...
2010: PloS One
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