Food and Behaviour Research

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A high-fat diet promotes depression-like behavior in mice by suppressing hypothalamic PKA signaling

Vagena E, Ryu JK, Baeza-Raja B, Walsh NM, Syme C, Day JP, Houslay MD, Baillie GS (2019) Transl Psychiatry.  2019 May;9(1): 141. doi: 10.1038/s41398-019-0470-1. 

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Obesity is associated with an increased risk of depression. The aim of the present study was to investigate whether obesity is a causative factor for the development of depression and what is the molecular pathway(s) that link these two disorders.

Using lipidomic and transcriptomic methods, we identified a mechanism that links exposure to a 
high-fat diet (HFD) in mice with alterations in hypothalamicfunction that lead to depression. Consumption of an HFD selectively induced accumulation of palmitic acid in the hypothalamus, suppressed the 3', 5'-cyclic AMP (cAMP)/protein kinase A (PKAsignaling pathway, and increased the concentration of free fatty acid receptor 1 (FFAR1). Deficiency of phosphodiesterase 4A (PDE4A), an enzyme that degrades cAMP and modulates stimulatory regulative G protein (Gs)-coupled G protein-coupled receptor signaling, protected animals either from genetic- or dietary-induced depression phenotype.

These findings suggest that dietary intake of saturated fats disrupts 
hypothalamic functions by suppressing cAMP/PKA signaling through activation of PDE4A. FFAR1 inhibition and/or an increase of cAMP signaling in the hypothalamus could offer potential therapeutic targets to counteract the effects of dietary or genetically induced obesity on depression.


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