Other brain areas involved in the depression-related behaviors, such as the cortex, hippocampus, and cerebellum, also showed no differences in PDE4 activity differences among mice fed either an ND or HFD (Supplementary Fig. S4C-E), further suggesting that the hypothalamus is a key locus affected in obesity-induced depression that leads to the upregulation of PDE4 activity. Here, PDE4A is linked to major depressive disorder.