Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type-2 diabetes (T2D) 1–3. While 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 4–6. Yet, no direct connection between the obesity-associated variants and FTO expression or function has been made 7–9. 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. Supporting this, obesity-associated SNPs are associated with expression of IRX3, but not FTO, in human brains. Directly linking IRX3 expression with regulation of body mass and composition, Irx3-deficient mice exhibit a 25–30% reduction in body weight, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Furthermore, hypothalamic expression of a dominant negative form of Irx3 reproduces the metabolic phenotypes of Irx3-deficient mice. Our data posit that IRX3 is a functional long-range target of obesity-associated variants within FTO, and represents a novel determinant of body mass and composition.

Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central for type 2 diabetes pathogenesis, and therefore understanding islet genome regulation could provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity, and show that most such sequences reside in clusters of enhancers that form physical 3D chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers, and identify trait-associated variants that disrupt DNA-binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome, and provide systematic evidence that dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.