Natural genetic variation and loss of function studies provide compelling support for this hypothesis; NR3C1, RARB, LMO3, FOXO4, TEAD1, FOXD1, AR, THRB, RORC, TBX15, TWIST1, TCF7L2, SHOX2, HOXC13, IRX3 and IRX5 are each phenotypically linked to adipose tissue functions, body fat distribution, obesity or type 2 diabetes [24, 27, 29, 96–99]. Here, IRX5 is linked to obesity due to melanocortin 4 receptor deficiency.