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

Vagena, E., Ryu, J. K., Baeza-Raja, B., Walsh, N. M., Syme, C., Day, J. P., Houslay, M. and Baillie, G. (2019) A high-fat diet promotes depression-like behavior in mice by suppressing hypothalamic PKA signalling. Translational Psychiatry, 9(1), 141. (doi: 10.1038/s41398-019-0470-1) (PMID:31076569) (PMCID:PMC6510753)

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Abstract

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 hypothalamic function 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 (PKA) signaling 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.

Item Type:Articles
Additional Information:The present study was supported by an Onassis Foundation Predoctoral Fellowship (E.V.); Medical Research Council grants G0600765 and J007412 (G.S.B.); and National Center for Research Resources Grant RR18928 (Gladstone Institute of Neurological Disease).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Houslay, Professor Miles and Walsh, Nicola and Day, Dr Jonathan
Authors: Vagena, E., Ryu, J. K., Baeza-Raja, B., Walsh, N. M., Syme, C., Day, J. P., Houslay, M., and Baillie, G.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Translational Psychiatry
Publisher:Nature Publishing Group
ISSN:2158-3188
ISSN (Online):2158-3188
Published Online:10 May 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Translational Psychiatry 9(1):141
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765RI NEUROSCIENCE & PSYCHOLOGY
588611cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.George BaillieMedical Research Council (MRC)MR/J007412/1RI CARDIOVASCULAR & MEDICAL SCIENCES