Obesity-associated variants within FTO form long-range functional connections with IRX3
Open accessAbstract
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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In obesity susceptibility, trait-associated SNPs are located within the intron of the FTO gene but lead to the dis-regulation of the distal IRX3 gene.
“A classic example is in obesity susceptibility, where trait-associated SNPs are located within the intron of the FTO gene, but lead to the dis-regulation of the distal IRX3 gene [210].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [210]
The paper’s Abstract places obesity-associated SNPs in FTO introns and reports that they are associated with IRX3 expression in human brain. It also describes a long-range functional connection to IRX3, but treats the possibility that the variants disrupt enhancer activity and alter expression as a possibility; it does not establish the claim’s causal wording that the SNPs lead to IRX3 dysregulation. No page number is supplied in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe strongest associated obesity GWAS signal lies within an intron of FTO but principally influences expression of distal genes IRX3 and IRX5.
“One such example comes from the strongest associated obesity GWAS signal that lies within an intron of the FTO gene, but principally influences the expression of distal genes IRX3 and IRX517–19.”
From Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicates <i>RTFDC1</i> at the <i>CASS4</i> locus (2024) · cites this paper as [17]
The paper’s main text (indexed as Abstract; page unavailable) reports that obesity-associated variants in an FTO intron are associated with IRX3 expression in human brain, but not FTO expression. The passages do not establish an effect on IRX5 expression or that this is the strongest obesity GWAS signal. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMore recent examples have focused on the relationship between obesity-associated variants intronic to FTO, altered expression of IRX3 and IRX5, and adipocyte and hypothalamic function.
“More recent examples have focused on the relationship between obesity-associated variants intronic to FTO, altered expression of IRX3 IRX5, and adipocyte102 and hypothalamic103 function.”
From A brief history of human disease genetics (2020) · cites this paper as [103]
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- Authors
- Smemo, S., Tena, J. J., Kim, K.-H., Gamazon, E. R., Sakabe, N. J., Gómez-Marín, C., Aneas, I., Credidio, F. L., Sobreira, D. R., Wasserman, N. F., Lee, J. H., Puviindran, V., Tam, D., Shen, M., Son, J. E., Vakili, N. A., Sung, H.-K., Naranjo, S., Acemel, R. D., Manzanares, M., Nagy, A., Cox, N. J., Hui, C.-C., Gomez-Skarmeta, J. L., & Nóbrega, M. A.
- Affiliations
- University of Chicago (US)
- Consejo Superior de Investigaciones Científicas (ES)
- University of Toronto (CA)
- Mount Sinai Hospital (CA)
- Spanish National Centre for Cardiovascular Research (ES)
- Corresponding author
- Hui, Chi-Chung
- Nóbrega, Marcelo A.
- ORCID
- Venue
- Nature
- Published
- 2014-03-12
- Volume
- 507
- Issue
- 7492
- Pages
- 371-375
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4113484
- OpenAlex
- W2156714600
- Cited by
- 1,219
- References
- 53
- Citations by year
- 2026: 37 · 2025: 59 · 2024: 78 · 2023: 75 · 2022: 80 · 2021: 104 · 2020: 99 · 2019: 114 · 2018: 103 · 2017: 135 · 2016: 124 · 2015: 139 · 2014: 71 · 2013: 1
- FWCI
- 64.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Heart and Stroke Foundation of Canada
- National Institutes of Health (DK020595)
- Canadian Institutes of Health Research
- National Heart, Lung, and Blood Institute (R01HL114010, HL119967, R01HL119967, HL114010, T32HL007381)
- National Institute of Mental Health (R01MH090937, R01MH101820, MH101820, MH090937)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK093972, DK 20595, DK020595, P60DK020595, R01DK093972, P30DK020595)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54AR052646)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- obesity, FTO, IRX3, long-range enhancers, non-coding variants, gene expression regulation, homeobox genes, type 2 diabetes, body mass, white adipose tissue browning, basal metabolic rate, diet-induced obesity, fat mass, brain gene expression, single nucleotide polymorphisms, zebrafish, promoter interactions
- MeSH terms
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Adipose Tissue, Animals, Basal Metabolism, Body Weight, Brain, Diabetes Mellitus, Type 2, Diet, Genes, Dominant, Humans, Mixed Function Oxygenases, Hypothalamus, Introns, Oxo-Acid-Lyases, Male, Obesity, Phenotype, Promoter Regions, Genetic, Proteins, Thinness, Transcription Factors, Zebrafish, Body Mass Index, Homeodomain Proteins, Polymorphism, Single Nucleotide, Mice
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