High Fat Diets Weigh On The Brain

“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,” says George Baillie, PhD, as published in Translational Psychiatry. “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. 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.”

Those with depression are less likely to respond well to current antidepressant drugs if they are also overweight or obese, findings point to potential targets for development of antidepressants which may be more effective for overweight or obese patients who are also suffering with depression.

Neurobiology involves different brain regions in depression and obesity, however the hypothalamus has been implicated in obesity and depression; cyclic AMP signaling is thought to play roles in pathophysiology and pharmacology of depression. Antidepressant drugs are thought to impact the cAMP signalling cascade to increase activity of cAMP dependent protein kinase A.

“Protein phosphorylation by PKA regulates a vast variety of neuronal functions, 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.”

A series of studies were carried out to investigate how diet and obesity may impact the development of depression, initial studies have demonstrated mice fed high fats diets to induce obesity developed depression like behaviors before they became obese; and depression was also observed to develop in a mouse model genetically engineered to become obese when fed a normal diet.

Consumption of high amounts of fat correlated with changes to PKA signaling pathway in the hypothalamus based on results from gene expression analysis; both diet induced and genetically induced obesity was associated with increased expression and activity of a form of PDE4 enzyme phosphodiesterase 4A5 in the hypothalamus. Development of depression was prevented by knocking out the mouse PDE4A gene in both mouse models even though the  high fat diet mice still gained weight; loss of PDE4A appeared to protect the animals from obesity associated depression phenotype.

Dietary fatty acids may be involved in the depression related hypothalamic signaling changes identified in the high fat diet mice; free fatty acids and palmitic acid in particular were found to accumulate in the hypothalamus of the HFD fed mice. Analyses of a neuronal cell line showed palmitic acid to suppress the PKA pathway.

Combined findings from research led by the University of Glasgow indicates palmitic acid intake as part of a HFD collects in the hypothalamus which disrupts its functions by suppressing cAMP/PKA signaling through activation of PDE4A. “… 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.”

“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. 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.”

“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. 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.”