The link between obesity and depression has long been known, but the mechanisms that underpin how one may cause the other haven’t been understood. Studies in mice by a University of Glasgow-led research team have now shown how fatty acids consumed as part of a high-fat diet (HFD) travel via the bloodstream into the hypothalamus region of the brain, and impact directly on signaling pathways associated with depression, even before obesity develops. “We all know that a reduction in fatty food intake can lead to many health benefits, but our research suggests that it also promotes a happier disposition,” commented research lead George Baillie, PhD, professor of molecular pharmacology.

Depressed patients who are obese are less likely to respond well to existing antidepressant drugs, and the new findings also point to potential targets for the development of antidepressants that might be more effective than current treatments for overweight or obese patients. The research, reported today in Translational Psychiatry, demonstrated that reducing expression of the gene encoding phosphodiesterase 4A (PDE4A) in mice was enough to protect animals from developing symptoms of obesity-linked depression.

“This is the first time anyone has observed the direct effects a high-fat diet can have on the signaling areas of the brain related to depression,” stated Baillie. “This research may begin to explain how and why obesity is linked with depression and how we can potentially better treat patients with these conditions.” The researchers reported their findings in a paper titled “Dietary fats entering the brain may explain link between obesity and depression.”

Both epidemiological and clinical studies have linked obesity with depression, but how the two states might be causally linked isn’t understood, the researchers wrote. “Even though a positive association between obesity and depression has been established which of the two plays a causative role for the development of the other one and what is the molecular mechanism(s) of this phenomenon remains unknown.” Overweight and/or obese depressed patients respond less well to antidepressants than individuals of a normal weight, and this suggests that unique molecular pathways for depression may be active in overweight and obese individuals.

While the complex neurobiology of depression involves different brain regions, the hypothalamus has been implicated in both depression and obesity, and cyclic AMP (cAMP) signaling is thought to play a key role in the pathophysiology and pharmacology of depression, the researchers further explained. Current antidepressant drugs are believed to impact on the cAMP signaling cascade, increasing the activity of cAMP-dependent protein kinase A (PKA). “Protein phosphorylation by PKA regulates a vast variety of neuronal functions,” the investigators added. A role for phosphodiesterase enzymes that degrade cAMP has also been suggested. “In depression, signaling via cAMP may be impaired by cyclic nucleotide phosphodiesterases (PDEs) … Of all the different PDEs, members of the PDE4 gene family play a major role in regulating cognition and depressive disorders.”

Working with collaborators at the Institute of Pharmaceutical Science, King’s College London, and the Gladstone Institute of Neurological Disease, University of California, San Francisco, the University of Glasgow-led team carried out a series of studies to investigate how diet and obesity may impact on the development of depression. Their initial studies demonstrated that mice fed a high-fat diet to induce obesity developed depression-like behaviors, even before they became obese. Depression also developed in a mouse model that is genetically engineered to become obese when fed a normal diet.

Gene expression analyses suggested that consumption of high amounts of fat correlated with changes to the PKA signaling pathway in the hypothalamus. “Genes regulating the PKA signaling pathway were significantly decreased after 8 weeks on an HFD,” the investigators wrote. “ … the consumption of an HFD regulates the PKA signaling pathway in the hypothalamus and might be responsible for the development of the obesity-induced depression-like phenotype in mice.”

Further analyses also showed that both diet-induced and genetically induced obesity was associated with increased expression and activity of one form of the phosphodiesterase 4 (PDE4) enzyme, phosphodiesterase 4A5 in the hypothalamus. (In humans the cognate enzyme is called PDE4A4.) Knocking out the mouse PDE4A gene in both diet-induced and genetic models of obesity prevented the development of depression, even though the HFD-fed animals still put on weight. “… loss of PDE4A protects mice from obesity-associated depression phenotype, despite similar weight gains in response to an HFD,” the scientists stated.

Hypothesizing that dietary fatty acids may somehow be involved in the depression-related hypothalamic signaling changes identified in HFD-fed mice, the team found that free fatty acids (FFA), and in particular palmitic acid, accumulated in the hypothalamus of mice fed a high-fat diet. Further analyses in a neuronal cell line showed that palmitic acid suppressed the PKA pathway. The results collectively indicated that the palmitic acid consumed as a part of a high-fat diet collects in the hypothalamus and disrupts hypothalamic functions by suppressing cAMP/PKA signaling through the activation of PDE4A.

“The present study reveals that the accumulation of different fatty acids in the hypothalamus alters PKA signaling, suggesting a potential mechanism of action of dietary fatty acids in the regulation of mood disorders, such as depression, via the PKA signaling pathway,” the authors concluded. “To the best of our knowledge, the present findings are the first to show that the consumption of an HFD induces an influx of dietary fatty acids specifically in the hypothalamus, leading to an impairment of the cAMP/PKA signaling cascade and this downregulation of the PKA pathway can be implicated behaviorally for the development of depression in mice.”

The authors suggest that their results could also help to direct the development of new antidepressants that are more effective in obese or overweight patients. “… small molecules that selectively target the interaction of the PDEs with free fatty acid receptors might represent a new generation of antidepressants with increased specificity for either overweight and/or obese individuals.”

“We often use fatty food to comfort ourselves as it tastes really good, however in the long term, this is likely to affect one’s mood in a negative way,” Baillie commented. “Of course, if you are feeling low, then to make yourself feel better you might treat yourself to more fatty foods, which then would consolidate negative feelings … understanding the types of fats, such as palmitic acid, which are likely to enter the brain and affect key regions and signaling will give people more information about how their diet can potentially affect their mental health.”