Most of the marker genes associated with obesity are expressed in the brain and not in the rest of the body.
Researchers have long known that various small differences in human genes are associated with the risk of developing obesity. These are called genetic variants, and they interact with environmental factors to change how genes are expressed just enough that some people accumulate a little more fat month after month.
However, these genes are expressed in very few cell populations in a limited number of tissues.
You could guess in which parts of the body the genes that predispose to severe obesity exert their effect.
Many people would think fat tissue, but they are probably wrong.
A new Danish study shows that most of the 750 marker genes that are associated with an increased risk of developing obesity are expressed in the brain and not in adipocytes or any other peripheral tissues.
“We have not previously been able to identify where specific genes are expressed in the many cells our bodies comprise because the individual cell populations are difficult to characterize at the molecular level. However, understanding how common obesity develops and how to effectively treat people and prevent obesity in the first place requires us to better understand what the actual biology is that is driving risk toward developing obesity. We can now show where in the body we should look to tease out that biology,” explains Tune H. Pers, Associate Professor and Group Leader, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
The discovery has been published in eLife.
Obesity-related genes only expressed in the brain
Tune H. Pers and colleagues combined obesity-related data from genome-wide association studies, which focus on the associations between how people differ genetically and in terms of their weight.
Data on the genes expressed in specific types of cells were obtained from mice, but Tune H. Pers explains that mice and people have quite similar gene expression patterns in terms of overall cell types across tissues, so a mouse model can advance researchers’ knowledge on the situation of humans.
The researchers analysed the massive quantity of data and found that the marker genes for developing obesity are expressed in very few types of cells.
Of the 727 types of peripheral and central nervous system cells spanning 17 mouse organs, the researchers found 26 that expressed genes near the genetic markers associated with obesity, and they were all in the brain and of neuronal origin.
“This indicates that the genetically related risk of developing obesity is primarily located in the brain,” says Tune H. Pers.
The brain is the command centre for metabolizing fat
Tune H. Pers says that, although all obesity-related gene variants appear to be primarily expressed in the brain, researchers may discover within a few years that some of these also function through fat tissue.
In addition, even though the genes are only expressed in the brain, the brain communicates with all the other tissues involved when people become obese, including fat tissue and the gut.
“The field of obesity is increasingly recognizing that understanding how obesity develops requires understanding the processes in the brain because it regulates all other tissues,” explains Tune H. Pers.
The brain controls fat tissue very precisely
Tune H. Pers explains that the brain and fat tissue are very clearly linked and that studying the brain in the search for solutions to the obesity epidemic therefore also makes sense – not only the brains of people with obesity but also normal-weight individuals who appear to be protected from developing obesity.
The animal kingdom also provides interesting phenomena in how fat tissue is regulated.
The brains of bears control very precisely how fat is metabolized during hibernation, so that they can survive a long winter without eating.
This also applies to certain migratory birds, such as the bar-tailed godwit, which feeds on clams and worms before travelling about 12,000 kilometres on its journey from Alaska to New Zealand. They fatten themselves up just before they leave, reduce all unnecessary energy consumption while migrating and use the last grams of fat as they land on the other side of the world.
We humans could be under the same strict constraint. The brain does not make arbitrary decisions about our fat depots but controls them very precisely to create a razor-sharp balance – if the whole system operates properly.
“People with normal weight have extremely constant weight because the brain continually ensures that they take in and add to the depot fat exactly what is required and no more. But if my brain is not in balance and misjudges how much I need to eat to maintain this constant weight, the idea that the brain potentially tells me that I need to store slightly more energy than I actually need to is appealing. Whether or not this theory can explain why so many people are overweight remains to be shown, but it is an intriguing explanation,” says Tune H. Pers.
Researchers were surprised about the relevant cells
Tune H. Pers reports that the cells with activity in the relevant genes are actually mostly outside the areas of the brain that they had expected. They had expected to find signals in the hypothalamus and hindbrain – two brain areas known to regulate eating behaviour – but found greater activity elsewhere.
The hindbrain stops us before we polish off the rest of the buffet, and the hypothalamus is the command centre for all communication with the rest of the body. Nevertheless, the activity was not greatest there.
The researchers instead found activity in the genes in the hippocampus, which is associated with memory, and in the part of the brain associated with regulating the integration of sensory stimuli.
“We found strong signals in the areas of the brain that integrate sight, taste and touch but a weaker signal in the areas that ensure that our weight remains stable. This discovery was interesting and surprising,” explains Tune H. Pers.
High-fat food changes the hippocampus
Tune H. Pers says that researchers not only know that the brain has the greatest role in developing obesity but can now also identify some of the areas in the brain in which this role originates.
The next step in the research is to understand what exactly happens when the brain, for various reasons, thinks it needs to accumulate more fat and deposit it in the fat cells than is actually needed.
Tune H. Pers describes an experiment in which people ate Belgian waffles and fast food every morning for a week, and this caused measurable changes in the hippocampus that made them more likely to subsequently choose high-fat foods instead of healthier food.
“This work along with other studies, suggests that the hippocampus plays a very important role in developing obesity. As you eat high-fat foods, the hippocampus and the brain demand even more high-fat foods, and this self-reinforcing effect can get out of control. With this study, we are slowly getting closer to understanding the biological reasons why so many people become obese and cannot shed this additional weight,” concludes Tune H. Pers.