In the current work, we have shown that obesity significantly elevated glucose and mRNA levels of Bace1, Psen2, Gsk3b, Sphk1, and Bax as well as pro-inflammatory Il1b, Il6, and Tnf, which was accompanied by downregulation of S1pr1 and pro-survival and anti-amyloidogenic Sirt1. Moreover, locomotor activity and behavioral parameters reflecting a form of spatial and episodic memory, such as spatially guided exploratory behavior and recognition, were impaired. Here, GSK3B is linked to obesity due to melanocortin 4 receptor deficiency.