This paper focuses on the biological functions and roles of GRP78 in weight control and energy restriction via regulating mitochondrial autophagy and adenosine monophosphate-activated protein kinase-PPARγ coactivator 1α-sirtuin1 (AMPK-PGC1α-SIRT1) signal pathway (Figure 1, Pathway 1), revealing the subcellular mechanisms of GRP78 in the pathogenesis of obesity and providing new evidence for effective treatment of obesity and related diseases. This evidence concerns the gene HSPA5 and Obesity.