Such studies may help to explain the overlapping disease phenotypes following ovariectomy [27,66], a pathologic naturally-occurring ERα deletion mutant that cannot bind oestrogen [68] and in ER and Sirt1 knockout mice; these conditions include insulin-resistance, the metabolic syndrome, Type 2 diabetes, obesity, infertility and loss of cognitive function [69–74]. This evidence concerns the gene ESR1 and obesity due to melanocortin 4 receptor deficiency.