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A High-fat Diet Promotes Depression-like Behavior in Mice by Suppressing Hypothalamic PKA Signaling

42 Pages Posted: 7 Jun 2018 Sneak Peek Status: Review Complete

See all articles by Eirini Vagena

Eirini Vagena

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease; University of Glasgow - Department of Molecular Pharmacology

Jae Kyu Ryu

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

Bernat Baeza-Raja

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

Nicola M. Walsh

University of Glasgow - Department of Molecular Pharmacology

Catriona Syme

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

Jonathan P. Day

University of Glasgow - Department of Molecular Pharmacology

Miles D. Houslay

University of Glasgow - Department of Molecular Pharmacology; University of London - Institute of Pharmaceutical Science

George S. Baillie

University of Glasgow - Department of Molecular Pharmacology

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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.

Suggested Citation

Vagena, Eirini and Ryu, Jae Kyu and Baeza-Raja, Bernat and Walsh, Nicola M. and Syme, Catriona and Day, Jonathan P. and Houslay, Miles D. and Baillie, George S., A High-fat Diet Promotes Depression-like Behavior in Mice by Suppressing Hypothalamic PKA Signaling (2018). Available at SSRN: https://ssrn.com/abstract=3188483 or http://dx.doi.org/10.2139/ssrn.3188483
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Eirini Vagena

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

University of Glasgow - Department of Molecular Pharmacology

Glasgow, Scotland G12 8QQ
United Kingdom

Jae Kyu Ryu

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Bernat Baeza-Raja

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Nicola M. Walsh

University of Glasgow - Department of Molecular Pharmacology

Glasgow, Scotland G12 8QQ
United Kingdom

Catriona Syme

University of California, San Francisco (UCSF) - Gladstone Institute of Neurological Disease

1650 Owens Street
San Francisco, CA 94158
United States

Jonathan P. Day

University of Glasgow - Department of Molecular Pharmacology

Glasgow, Scotland G12 8QQ
United Kingdom

Miles D. Houslay

University of Glasgow - Department of Molecular Pharmacology

Glasgow, Scotland G12 8QQ
United Kingdom

University of London - Institute of Pharmaceutical Science

150 Stamford Street
London, England SE1 9NH
United Kingdom

George S. Baillie (Contact Author)

University of Glasgow - Department of Molecular Pharmacology ( email )

Glasgow, Scotland G12 8QQ
United Kingdom

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