FTO Obesity Variant Circuitry and Adipocyte Browning in Humans

By M. Claussnitzer, S. Dankel, Kyoung-Han Kim, G. Quon, W. Meuleman, Christine Haugen, V. Glunk, Isabel S. Sousa, Jacqueline L Beaudry, V. Puviindran and 9 more. New England Journal of Medicine, 2015

1,268 citations recorded by the source corpus.

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. We validated our predictions with the use of directed perturbations in samples from patients and from mice and with endogenous CRISPR–Cas9 genome editing in samples from patients. RESULTS Our data indicate that the FTO allele associated with obesity represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The rs1421085 T-to-C single-nucleotide variant disrupts a conserved motif for the ARID5B repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of IRX3 and IRX5 expression during early adipocyte differentiation. This results in a cell-autonomous developmental shift from energy-dissipating beige (brite) adipocytes to energy-storing white adipocytes, with a reduction in mitochondrial thermogenesis by a factor of 5, as well as an increase in lipid storage. Inhibition of Irx3 in adipose tissue in mice reduced body weight and increased energy dissipation without a change in physical activity or appetite. Knockdown of IRX3 or IRX5 in primary adipocytes from participants with the risk allele restored thermogenesis, increasing it by a factor of 7, and overexpression of these genes had the opposite effect in adipocytes from nonrisk-allele carriers. Repair of the ARID5B motif by CRISPR–Cas9 editing of rs1421085 in primary adipocytes from a patient with the risk allele restored IRX3 and IRX5 repression, activated browning expression programs, and restored thermogenesis, increasing it by a factor of 7. CONCLUSIONS Our results point to a pathway for adipocyte thermogenesis regulation involving ARID5B, rs1421085, IRX3, and IRX5, which, when manipulated, had pronounced pro-obesity and anti-obesity effects. (Funded by the German Research Center for Environmental Health and others.)

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Citations in the corpus

An expanded view of complex traits: from polygenic to omnigenic (2017, background): “, 2012), and roles for adipocyte thermogenesis (Claussnitzer et al., 2015) and central nervous system genes in obesity (Locke et al.”
Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets (2016, background): “Unfortunately, this hypothesis has not yet been tested empirically because of the lack of comprehensive follow-up functional studies for GWAS discoveries, and there have been examples in recent studies 2,3 suggesting that causal genes are distinct from the nearest genes.”
Detection and interpretation of shared genetic influences on 42 human traits (2016, unknown): “Regulatory variants in an intron of the FTO gene 49;50 that are associated with breast size in women (Supplementary Figure 12: rs1421085 s.d., P = 3.5 × 10 −7 ) and age at voice drop in men ( s.d., P = 2.7 × 10 −5 ), among others.”
Orienting the causal relationship between imprecisely measured traits using GWAS summary data (2017, background): “complex traits are, by design, hypothesis free and agnostic of genomic function, and it often takes years of follow up studies to understand the biological nature of a putative GWAS hit [29].”
Functionally-informed fine-mapping and polygenic localization of complex trait heritability (2019, background): “Third, the proximal pairs of coding and noncoding fine-mapped SNPs that we identified (Supplementary Table 25) may aid efforts to link SNPs to genes 51– 53 .”
Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects (2020, methodology): “rs1421085 can be edited using the CRISPR/Cas9 platform to repair the pattern structure of ARID5B, thereby suppressing the expression of IRX3 and IRX5 and achieving the effect of weight loss.(106) As an important “experimental tool”, the animal model of diabetes can be used for pathological observati”
Meta-analysis of genome-wide association studies for height and body mass index in ∼700,000 individuals of European ancestry (2018, unknown): “They have also been used to generate experimentally testable hypotheses and predict traits and disease risk (7,8).”
The Human Transcription Factors. (2018, unknown): “…example, an intronic obesity-associated polymorphism in the FTO locus alters enhancer function by modulating the binding of ARID5B, leading to an increase in IRX3 and IRX5 expression, changing adipocyte cell fate and overall mitochondrial thermogenesis in adipose tissue (Claussnitzer et al., 2015).”