Only a few weeks ago I looked at a study on fast food consumption and depression, and only a few days ago I talked about a brand new study looking at high fat diets and protection from heart attack damage. And today, we've got another study on high fat diet, this time in mice, and depressive-like behavior. What is the effect of a high fat diet? Well, it appears to be getting more complicated with each new study.

But it this study, at least, it looks like diet-induced obesity might produce depressive-like effects in mice. But how the diet is doing that is not so well defined.

Sharma and Fulton. "Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry" International Journal of Obesity, 2012.

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Several studies in humans have found a correlation between obesity and the development of depression. But it's important to keep in mind that correlation is not causation. Many people who become obese also have other things going on (socioeconomic status, family history, comorbid disorders) which can influence the development of depression. In order to determine if obesity itself is causing depression, you first have to deliberately cause obesity in a controlled population.

And this is where mice come in. Using a specialty high fat and high sugar diet, Sharma and Fulton fed up a set of mice for 12 weeks, until they were significantly fatter than control mice. They then looked at behavioral tests for anxiety and depression.

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What you can see above are different behavioral tests. The top two panels represent the elevated plus maze, a plus shaped design with two open arms and two closed arms. Mice prefer to stay in the closed arms of the maze, because they prefer darkness and small spaces. The more anxious a mouse is, the more time he will spend in the closed arms. In this case, the mice fed on a high-fat diet spent more time in the closed arms of the maze.

In the second set of bars, the open field, the findings were similar. The mouse is placed in a large open field. He will usually stay out of the center, preferring the more protected edges and corners. The more anxious a mouse is, the more he will stay to the edges of the field. Again, the high-fat diet mice stayed on the edges more than normal mice suggesting that high-fat diets make mice more anxious.

However, anxiety tests are not depression. For their main depression measure (the bottom set of bars), the authors used the forced swim test, where a mouse is placed in a bucket of water and swims for a few minutes. After a while it will realize it can't get out and begin to float, a sign of "behavioral despair". Mice given antidepressants will swim more and float less, and mice showing depressive-like behavior will float more. In this case, the high fat diet mice floated more than control mice, which the authors suggest is depressive like behavior.

High-fat diet mice showed other alterations as well. Depressive-like behavior has been correlated in the past with changes in stress-responses, so the authors looked at the stress hormone corticosterone (which is cortisol in humans). High-fat diet mice showed slightly higher corticosterone, but much higher levels after stress, suggesting that they may be more sensitive to stress than normal mice.

The authors also looked at alterations in reward pathways like the nucleus accumbens and striatum, and found significant changes. Though changes in these areas are not usually correlated with depressive-like behavior, they have been shown in other high fat studies and are thought to relate to differences in how animals eating high fat diets process rewards.

From these data the authors conclude that their high-fat diet obesity produced depressive-like behavior. And while I think the preliminary data has potential, I also think there could be improvements.

First off, they did not look at other tests of depressive-like behavior in mice, such as sucrose drinking or novelty-induced hypophagia. The forced swim test could be confounded by the fact that fat mice might have a harder time swimming.

Secondly, I would have liked to see more work done in areas which are known to be correlated with depressive-like behavior. For example, chronic stress is associated with depressive-like behavior and decreases in neurogenesis, something which can be improved with antidepressants. Does a high-fat diet produce decreases in neurogenesis? Changes in reward-related areas are fine, but that's only one aspect, and not really what people focus on for depressive-like behavior.

Third, I think I would like to see this study performed...before the mice are fat. They gave the diet for 12 weeks and got fat mice, and that's fine, but this diet also begins to produce things like insulin resistance typical of type 2 diabetes. And previous studies have shown that type 2 diabetes is also associated with depressive-like behavior, which could influence their results. I wonder what would happen after 6 weeks of high fat diet, when they've had plenty of exposure but aren't yet obese?

Finally, like any good scientist, I wonder: what is the mechanism? HOW exactly does a high fat diet or obesity lead to depressive behavior? Is it the corticosterone and stress levels? If so, how is a high fat diet influencing the HPA axis? If not, what else is changing? Dopaminergic systems and reward are nice but are certainly not the whole story. Future studies will have to tell. But it does make me wonder what a high fat and high sugar diet might be doing, and what exactly is going on.

Sharma, S., & Fulton, S. (2012). Diet-induced obesity promotes depressive-like behaviour that is associated with neural adaptations in brain reward circuitry International Journal of Obesity DOI: 10.1038/ijo.2012.48