We found that GPER1 acts a crucial role in the metabolic disorders, including obesity, insulin resistance, and hepatic lipid accumulation in female mice and plays a crucial effect in the protective effect of E2 against palmitic acid (PA) and oleic acid (OA) mixture (PO)-challenged lipid accumulation, oxidative stress, and inflammation in hepatocytes. The gene discussed is GPER1; the disease is obesity due to melanocortin 4 receptor deficiency.