Against the background of the potentially life-threatening side effects observed in the clinical use of PPARγ classical agonists such as the glitazones [42–46], that in comparison strongly stabilize H12 [114, 115], these findings launched a new era for PPARγ-targeting pharmacotherapeutics for the treatment of metabolic disease, in which the focus has shifted towards the development of potent inhibitors of Ser273 phosphorylation, that display little or no classical agonism [123, 127, 164–166]. This evidence concerns the gene PPARG and metabolic disease.