In contrast, long-term GRP78 under-expression in heterozygous (+/−) GRP78 knockout mice conferred protection from obesity and insulin resistance after exposure to high-fat diet [40]; in that study, high fat diet activated other chaperones of the adaptive UPR, thereby improving ER quality control and perhaps contributing to metabolic protection. The gene discussed is HSPA5; the disease is obesity due to melanocortin 4 receptor deficiency.