Here, we utilize 3D human cerebral organoids and 2D neural progenitor cells derived from human embryonic stem cells harboring WFS1 deficiency and Wfs1 conditional knockout mice (Wfs1flox/flox X Nestin‐Cre, CKO) exposed to HFD to examine the vicious cycle of obesity and depression. Here, WFS1 is linked to obesity due to melanocortin 4 receptor deficiency.