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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genome-wide association studies identified noncoding SNPs associated with type 2 diabetes and obesity in linkage disequilibrium (LD) blocks encompassing HHEX-IDE and introns of CDKAL1 and FTO [Sladek R, et al. (2007) Nature 445:881-885; Steinthorsdottir V, et al. (2007) Nat. Genet 39:770-775; Frayling TM, et al. (2007) Science 316:889-894]. We show that these LD blocks contain highly conserved noncoding elements and overlap with the genomic regulatory blocks of the transcription factor genes HHEX, SOX4, and IRX3. We report that human highly conserved noncoding elements in LD with the risk SNPs drive expression in endoderm or pancreas in transgenic mice and zebrafish. Both HHEX and SOX4 have recently been implicated in pancreas development and the regulation of insulin secretion, but IRX3 had no prior association with pancreatic function or development. Knockdown of its orthologue in zebrafish, irx3a, increased the number of pancreatic ghrelin-producing epsilon cells and decreased the number of insulin-producing beta-cells and glucagon-producing alpha-cells, thereby suggesting a direct link of pancreatic IRX3 function to both obesity and type 2 diabetes.
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PMID:Long-range gene regulation links genomic type 2 diabetes and obesity risk regions to HHEX, SOX4, and IRX3. 2008 Jul 51

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. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant-negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.
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PMID:Obesity-associated variants within FTO form long-range functional connections with IRX3. 2495 67

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. We and others have shown that in vitro, recombinant FTO is able to catalyse the Fe(II)- and 2OG-dependent demethylation of single stranded nucleic-acids, with a preference for RNA. We have shown that FTO expression is regulated by essential amino acids (AAs) and that it couples amino acid levels to mammalian Target of Rapamycin Complex 1 (mTORC1) signalling, through a mechanism dependent on its ability to demethylate. Thus FTO is an AA sensor and plays a key role regulating appropriate growth and translation. However, recent data focussing on obesity associated variants within FTO have implicated two neighbouring genes, RPGRIP1L and IRX3, as having a functional link between the SNP and the observed human phenotypes. As with Fto, perturbing the expression of these genes in mice results in a bodyweight phenotype, with homozygous deletion of Irx3 resulting in a smaller mouse and heterozygous deletion of Rpgrip1l leading to a mild obesity phenotype. Thus it may be that a number of genes in this region play an important role in determining body composition.
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PMID:The role of the FTO (Fat Mass and Obesity Related) locus in regulating body size and composition. 2522 90

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. Here, we undertake live cell imaging of GFP (green fluorescent protein)-FTO, and demonstrate that FTO resides in both the nucleus and cytoplasm. We show using 'FLIP' (fluorescence loss in photobleaching) that a mobile FTO fraction shuttles between both compartments. We performed a proteomic study and identified XPO2 (Exportin 2), one of a family of proteins that mediates the shuttling of proteins between the nucleus and the cytoplasm, as a binding partner of FTO. Finally, using deletion studies, we show that the N-terminus of FTO is required for its ability to shuttle between the nucleus and cytoplasm. In conclusion, FTO is present in both the nucleus and cytoplasm, with a mobile fraction that shuttles between both cellular compartments, possibly by interaction with XPO2.
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PMID:Fat mass and obesity-related (FTO) shuttles between the nucleus and cytoplasm. 2524 86

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. Here, we review these new findings and consider the implications for future analysis of GWAS hits.
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PMID:Obesity and FTO: Changing Focus at a Complex Locus. 2544

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. Our results indicate that Fto deficiency increases the expression of genes related to adipogenesis preventing adipocytes from becoming hypertrophic after high-fat diet. In addition, we report a novel finding of increased Irx3 expression in Fto-deficient mice after high-fat feeding indicating a complex link between FTO, IRX3 and fat metabolism.
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PMID:Fat mass- and obesity-associated gene Fto affects the dietary response in mouse white adipose tissue. 2578 72

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. The light-induced phase shifts of circadian rhythms were also significantly affected in FTO deficient mice. Tissue explants of FTO deficient mice maintained robust peripheral rhythms with prolonged period. Overexpress of FTO represses the transcriptional activation by CLOCK and BMAL1. Core clock genes expression of mRNA and protein were also altered in FTO deficient mice. Furthermore, FTO co-immunoprecipitated with CRY1/2 in a circadian manner. These results indicate a fundamental link between the circadian rhythm and FTO and extend the function of FTO to the core clockwork machinery.
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PMID:FTO modulates circadian rhythms and inhibits the CLOCK-BMAL1-induced transcription. 2618 89

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. In order to identify potential enhancers at the human FTO locus in vivo, we tested regulatory activity in FTO intron 1 using BAC transgenesis in zebrafish. A minimal gata2 promoter-GFP cassette was inserted 1.3 kb upstream of the obesity associated SNP rs9939609 in a human FTO BAC plasmid. In addition to the previously identified expression domains in notochord and kidney, human FTO BAC:GFP transgenic zebrafish larvae expressed GFP in the ventral posterior tuberculum, the posterior hypothalamus and the anterior brainstem, which are also expression domains of zebrafish irx3a. In contrast, an in-frame insertion of a GFP cassette at the FTO start codon resulted in weak ubiquitous GFP expression indicating that the promoter of FTO does likely not react to enhancers located in the obesity risk-associated region.
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PMID:BAC transgenic zebrafish reveal hypothalamic enhancer activity around obesity associated SNP rs9939609 within the human FTO gene. 2627 Oct 4

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. These findings provide a genomic model for the functional implications of genetic variations at this locus, and also demonstrate the importance of accounting for chromatin-chromatin interactions when constructing hypotheses for the mechanisms of trait and disease-associated common genetic variants. Several consortia have generated genome-wide datasets describing different aspects of chromatin biology which can be utilized to predict functionality and propose biologically relevant descriptions of specific DNA regions. Here, we review some of the publically available data resources on genome function and organization that can be used to gain an overview of genetic regions of interest and to generate testable hypotheses for future studies. We use the BMI- and obesity-associated FTO locus as a subject as it poses an illustrative example on the value of these resources. We find that public databases strongly support long-range interactions between regulatory elements in the FTO locus with the IRXB cluster genes IRX3 and IRX5. Chromatin configuration capture data also support interactions across a large region stretching across from the RPGRIP1L gene, FTO and the IRXB gene cluster.
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PMID:Scrutinizing the FTO locus: compelling evidence for a complex, long-range regulatory context. 2634 Sep 2

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. FTO is an FE (II) and 2-oxoglutarate dependent DNA/RNA methylase. Contrasting the impact of the SNPs on energy balance in humans, knocking out or reducing activity of the Fto gene in the mouse resulted in lowered adiposity, elevated energy expenditure with no impact on food intake (but the impact on expenditure is disputed). In contrast, overexpression of the gene in mice led to elevated food intake and adiposity, with no impact on expenditure. In rodents, the Fto gene is widely expressed in the brain including hypothalamic nuclei linked to food intake regulation. Since its activity is 2-oxoglutarate dependent it could potentially act as a sensor of citrate acid cycle flux, but this function has been dismissed, and instead it has been suggested to be much more likely to act as an amino acid sensor, linking circulating AAs to the mammalian target of rapamycin complex 1. This may be fundamental to its role in development but the link to obesity is less clear. It has been recently suggested that although the obesity related SNPs reside in the first intron of FTO, they may not only impact FTO but mediate their obesity effects via nearby genes (notably RPGRIP1L and IRX3).
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PMID:The 'Fat Mass and Obesity Related' (FTO) gene: Mechanisms of Impact on Obesity and Energy Balance. 2662 93


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