When most of us think about losing or gaining weight, we think about two things: the food we eat and the physical activity we do. Most of us assume that these two factors are independent – that is, the food you eat doesn’t affect the amount of energy you burn from physical activity. However, in a paper published last month in Cell Metabolism, we found that a high-fat diet actually changes the brains of mice to make them less physically active.
We started by putting a large group of mice on one of two diets: their standard low-fat “chow” or a palatable “high-fat” diet. We let the mice eat as much as they wanted until the high-fat diet mice weighed substantially more than the chow group. At this point, the obese, high-fat diet mice moved a lot less than the lean mice that had only eaten chow. Many people would assume that this was because the weight of the obese mice made it difficult for them to move. However, we had another idea.
Our study, and many others, have found that obese mice have decreased dopamine signaling in an area of the brain called the striatum. Therefore, we wondered if a decrease in dopamine signaling in our obese mice was responsible for their decreased physical activity. We found that obese mice had decreased dopamine D2 receptors, which are the proteins that detect dopamine levels in the brain. Although dopamine is often described in the context of pleasure, dopamine is also critical for movement. For example, patients with Parkinson’s disease lose the neurons that produce dopamine, which results in dysfunctional movement patterns.
The first thing we noticed was that there was a lot of variation in physical activity in our lean mice. Some mice would run on their running wheels for more than 5 miles per day, whereas others barely touched their wheels. Interestingly, the same was true for the obese mice. Although the average activity of the group dropped as they became obese, some mice stayed active even though they gained a lot of weight. If extra body fat makes mice too heavy to move, why are some obese mice still active? We hypothesized that the D2 receptor might be the explanation.
To test our prediction, we knocked down the dopamine D2 receptor in mice. To do this, we used a special line of mice that express molecular scissors only in certain brain cells. Where these scissors exist, they cut out part of the dopamine receptor gene so that the receptor is no longer functional. However, the rest of the brain remains untouched. Genetic tools like this allow neuroscientists to selectively manipulate genes and groups of cells to probe their specific functions in the brain.
Our genetically modified mice were lean, but had decreased dopamine signaling like the obese mice. We wanted to know, would these mice would move like lean mice or like obese mice? In fact, our lean mice without the dopamine receptor moved a lot less than normal mice, supporting our prediction that diminished dopamine signaling is responsible for decreased physical activity during obesity.
If dopamine signaling is responsible for decreased physical activity in our obese mice, then restoring that signaling should make obese mice active like lean mice. Using a technique called chemogenetics, we mimicked dopamine signaling in the brains of obese mice. Amazingly, they moved just like the lean mice. This excited us because it suggested that dopamine receptors control physical activity levels, even in obese mice.
Although it’s difficult to apply the findings from animal studies to humans, there are some key takeaways from our study. First, the food we eat can change the way we behave. This is an important, yet often overlooked, consideration in the ongoing debates over national food guidelines, school lunches, and genetically modified foods. Second, obese individuals have biologically different brains. More studies are needed to elucidate the full extent of these changes, but our study offers evidence that we should be cautious in our moral judgements about body weight. A few decades ago, most people believed that drug addiction was due to immorality and the lack of will power. Now, scientists understand that drug addiction is a disease of the brain. I believe we are due for a similar revolution in our understanding of obesity and other eating disorders. Finally, our study shows that it is possible to reverse these brain changes. This finding should provide hope for the millions of Americans who are overweight or obese, although it is not yet clear how to reverse obesity-induced brain changes in people.
There is so much that we do not understand about the brain circuits that control behavior. Neuroscientists are developing new ways to study the brain at breathtaking speeds. Understanding how the biology of our brains translates into action will increase our understanding of why it is so difficult to change our behavior through will power alone. But more importantly, it can also lead us to more effective strategies for combating many of our public health crises including addiction and obesity.