However, whether membrane ERα is involved in the protective metabolic actions of endogenous estrogens in conditions of nutritional challenge, and thus contributes to sex differences in the susceptibility to metabolic diseases, remains to be clarified.<h4>Methods</h4>Male and female <i>C451A-ERα</i> mice, harboring a point mutation which results in the abolition of membrane localization and MISS-related effects of the receptor, and their wild-type littermates (<i>WT-ERα</i>) were maintained on a normal chow diet (NCD) or fed a high-fat diet (HFD). The gene discussed is ESR1; the disease is metabolic disease.