The findings in animal experiment indicate that the secreted and membrane-bound forms of Gpnmb were produced from both WATs, liver macrophages, and stellate cells along with the development of obesity, they mainly localize with the macrophages and stellate cells in the liver by binding to cell-surface calnexin, and the Gpnmb exerted the protective effects against the development of fatty liver disease. The gene discussed is GPNMB; the disease is obesity due to melanocortin 4 receptor deficiency.