Variants in FTO have the strongest association with obesity; however, it is still unclear how those noncoding variants mechanistically affect whole-body physiology. We engineered a deletion of the rs1421085 conserved cis-regulatory module (CRM) in mice and confirmed in vivo that the CRM modulates Irx3 and Irx5 gene expression and mitochondrial function in adipocytes. The CRM affects molecular and cellular phenotypes in an adipose depot-dependent manner and affects organismal phenotypes that are relevant for obesity, including decreased high-fat diet-induced weight gain, decreased whole-body fat mass, and decreased skin fat thickness. Last, we connected the CRM to a genetically determined effect on steroid patterns in males that was dependent on nutritional challenge and conserved across mice and humans. Together, our data establish cross-species conservation of the rs1421085 regulatory circuitry at the molecular, cellular, metabolic, and organismal level, revealing previously unknown contextual dependence of the variant's action.
GrantsState of Bavaria Novo Nordisk Postdoctoral Research Fellowship Next Generation Award of the Broad Institute of MIT and Harvard German Center for Diabetes Research (DZD) UK Medical Research Council MRC University Unit programme Li Ka Shing Foundation WT-SSI/John Fell funds National Institute for Health Research Oxford Biomedical Research Centre Helmholtz Zentrum Munchen-German Research Center for Environmental Health - German Federal Ministry of Education and Research (BMBF) MRC PhD studentship