FIGURE 1.

IRX3 and IRX5 are effectors of FTO obesity-risk variants and key determinants of energy homeostasis. (A) IRX3 and IRX5 are located about a half-megabase downstream of FTO. In human brain, particularly hypothalamic arcuate nucleus (triangle with dashed lines in red) and preadipocytes, they mediate the effects of obesity-associated variants located in the first intron of FTO through long-range interactions. (B) Mice with mutations in Irx3 and/or Irx5 exhibit an anti-obesity phenotype with increased energy expenditure and reduced food intake. These metabolic phenotypes are related to beiging of white adipose tissue and improved response to leptin as well as increased postnatal neurogenesis in the mediobasal hypothalamus. Schematics were created using illustrations from https://biorender.com.