Wfs1 deficient CKO mice significantly increased expression of Atf4 and Znt3 in the hippocampus, cortex and hypothalamus (Figure S12A‐C, Supporting Information), suggesting that WFS1‐ZnT3‐Zn2+ axis regulates the vicious cycle of obesity and depression.  hypothalamus plays an essential role in controlling food intake and energetic status.[68, 69] Hypothalamic pro‐opiomelanocortin (POMC) neurons in hypothalamus have been reported to play a crucial role in regulating energy homeostasis and glucose/lipid metabolism. This evidence concerns the gene SLC30A3 and obesity due to melanocortin 4 receptor deficiency.