Global knockout ERα in mice recapitulate the phenotype of humans with rare inactivating receptor mutations and genetic polymorphisms in the receptor, which is exhibited by adiposity, reductions in energy expenditure and increased food intake, but they also exhibit glucose intolerance, insulin resistance, and reduced endothelial-derived nitric oxide production (vasculoprotective molecule), thus demonstrating the critical role for ESR1 in regulating energy, metabolic, and vascular homeostasis [155,159,160]. The gene discussed is ESR1; the disease is Insulin resistance.