BACKGROUND: Genomewide association studies can be used to identify disease-relevant genomic regions, but interpretation of the data is challenging. The @entity18957 region harbors the strongest genetic association with @entity28 , 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 @entity18957 region and @entity28 . We validated our predictions with the use of directed perturbations in samples from @entity1 and from @entity19 and with endogenous CRISPR-Cas9 genome editing in samples from @entity1 . RESULTS: Our data indicate that the @entity18957 allele associated with @entity28 represses mitochondrial thermogenesis in adipocyte precursor cells in a tissue-autonomous manner. The @entity40761 T-to-C single- @entity4334 variant disrupts a conserved motif for the @entity31983 repressor, which leads to derepression of a potent preadipocyte enhancer and a doubling of @entity61904 and @entity68721 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 @entity38928 in adipose tissue in @entity19 reduced body weight and @entity101 without a change in physical activity or appetite. Knockdown of @entity61904 or @entity68721 in primary adipocytes from @entity1 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 @entity31983 motif by CRISPR-Cas9 editing of @entity40761 in primary adipocytes from a @entity1 with the risk allele restored @entity61904 and @entity68721 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 @entity31983 , @entity40761 , @entity61904 , and @entity68721 , which, when manipulated, had pronounced pro- @entity28 and anti- @entity28 effects. (Funded by the German Research Center for Environmental Health and others.).

@entity18957 Obesity Variant Circuitry and Adipocyte Browning in XXXX .

@entity1 :: ('9606', 'Species') :: ['participants', 'patients', 'patient'] @entity18957 :: ('79068', 'Gene') :: ['FTO'] @entity101 :: ('MESH:D006973', 'Disease') :: ['increased energy dissipation'] @entity28 :: ('MESH:D009765', 'Disease') :: ['obesity'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity38928 :: ('16373(Tax:10090)', 'Gene') :: ['Irx3'] @entity61904 :: ('79191', 'Gene') :: ['IRX3'] @entity40761 :: ('rs1421085', 'SNP') :: ['rs1421085'] @entity31983 :: ('84159', 'Gene') :: ['ARID5B'] @entity68721 :: ('10265', 'Gene') :: ['IRX5'] @entity4334 :: ('D009711', 'Chemical') :: ['nucleotide']
@entity1 :: (9606,Species) :: ['Humans']
