What is the biological connection at the molecular level, if any, between depression and obesity? It is not unusual for people to over indulge in high-calorie foods in an attempt to improve their mood. However, consuming foods high in saturated fat such as candy bars, fries, hamburgers, chips, hot dogs, ice cream, and cookies may have the opposite effect.

Research has established the association between obesity and a higher risk for depression, but the exact mechanisms were not well understood. A recent neuroscience study, however, demonstrates how a diet high in saturated fats promotes depression-like behavior in mice by disrupting the functioning of the brain.

Published on May 10, 2019 in Translational Psychiatry, a study led by University of Glasgow professor George S. Baillie, along with research team of Miles D. Houslay, Jonathan P. Day, Catriona Syme, Nicola M. Walsh, Bernat Baeza-Raja, Jae Kyu Ryu, and Eirini Vagena, investigated the molecular underpinnings of obesity and depression using laboratory mice, and identified the brain’s hypothalamus as the connection.

The hypothalamus is the small area of the brain, about the size of an almond, that controls the pituitary glands and regulates many of the body’s metabolic processes, such as emotions, behavior, memory, hunger, thirst, weight, growth, circadian rhythms, libido, childbirth, breast milk production, salt/water balance, and body temperature.

The mice were put through a variety of behavior tests to measure the physical expression of the depression. The tests included an open field test for locomotor activity, tail suspension, forced swim test, sugar preference test, and a maze to measure anxiety-like behaviors in the mice.

The gene expression analysis included RNA extraction, reverse transcription, and real-time PCR. Microarray analysis was used on the mice’s hypothalamic brain region for gene expression profiling.

Using protein and mRNA analysis, the research team was able to identify PKA signaling as the main pathway changed in the hypothalamus of mice on a high-fat diet (HFD). The researchers discovered that laboratory mice fed high-fat diets had suppressed hypothalamic signaling and exhibited depression-like behavior.

Specifically, the cAMP (cyclic AMP) and PKA (protein kinase A) pathway was suppressed through activation of PDE4 (phosphodiesterase 4A)—an enzyme that is involved in the physical expression of depression-like traits (phenotype) brought on by obesity. To prevent depression-like behaviors, knock out PDE4A.

“PDE4 enzymes are major regulators of the cAMP signaling in the brain and localize in brain regions that are associated with reinforcement, movement, and affect, all of which actions are altered among people with depression,” wrote the researchers.

An enzyme is a molecule, usually a protein, that acts as a catalyst to speed up chemical reactions that occur in body cells. The cAMP/PKA pathway regulates cellular functions, and is a common signal pathway in eukaryotic cells. Eukaryotes are organisms that have one or more cells that have a membrane-bound nucleus and organelles—this includes animals, insects, plants, algae, fungi, and protists.

“Many antidepressant drugs act by upregulating molecules involved in cAMP signaling, which is the major regulator of PKA,” wrote the researchers in their study.

The scientists discovered that a high-fat diet increased the expression levels and activity of PDE4A in the hypothalamus, which raised the levels of free fatty acid receptor 1, and dampened cAMP/PKA signaling.

In other words, the consumption of a high-fat diet in the mice resulted in an increase in fatty acids in the hypothalamus which in turn, suppressed the PKA 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,” reported the researchers.

The findings in this groundbreaking research may pave the way for the development of a novel type of antidepressant to help obese patients suffering from depression in the future.

Psychology today

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