Danish researchers have characterized some of the areas in the brainstem that probably contribute to some people becoming obese. Some of the findings may represent targets for new treatments for obesity.
Although obesity becomes especially visible in the central regions of the body, the brain is actually the key area when people with a genetic predisposition to obesity continue to gain weight.
Long nerve fibres called the dorsal vagus complex from the intestine to the brain stem and the brainstem’s ability to detect hormones in the blood play an important role.
Using single-cell profiling techniques, Danish researchers have identified neuronal cells in the brain in which some of the genes for obesity are likely to be expressed.
This discovery advances knowledge about the cause of obesity, and the techniques may be used to identify new treatments for people with obesity.
“The genetic component of the cause of severe obesity is between 40% and 70%. However, not all the marker genes are expressed in all cells of the brain. In this study, we identified which cells in the brain may express some of the genes known to be associated with this genetic component,” explains the researcher initiating the study, Tune H. Pers, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen.
The research has been published in Nature Metabolism.
Gut and pancreatic hormones regulate the brain’s sensing neurons
Appetite-regulating receptors are key to the new study.
When you have eaten enough, your gut releases hormones that bind to receptors in the gut, which send signals along the dorsal vagus complex to the brainstem to indicate you that you are satiated.
However, people differ, and differences in genetics can result in some people ceasing to eat before others, and the people who stop very late can gain weight.
Within the past 10 years, researchers have obtained more knowledge on which genes are expressed when people become overweight. They have identified several genetic variants that increase the risk of becoming obese.
However, the researchers still need more knowledge.
Genes are not expressed in all cells, and understanding how genes play a role in developing obesity requires knowing the cells in the brain in which these genes are active.
“The neurons in the brain operate in specialized networks that perform various tasks. In this study, we used human genetics to identify some of the neurons that probably play an important role in developing obesity, at least the part that is genetically predisposed,” says Tune H. Pers.
Investigated associations of 750 genetic variants in 50,000 cells
The researchers used advanced techniques to characterize transcriptional activity in parts of the brainstems isolated from mice.
They compared this transcriptional activity with 750 genetic variants known to be associated with the development of obesity in humans. This enabled them to examine 50,000 cells in more than 30 cell clusters and identify the few cells that express most of the relevant genes.
“We removed the mice’s brainstems and isolated all cells and nuclei. Then we measured the messenger RNA in the nuclei to assay transcriptional activity and identify sets of genes that are specific to any of these cell types,” explains Tune H. Pers.
Genes predisposing for obesity expressed in four cell clusters in the brainstem
The researchers discovered the strongest signal in a type of cell that expresses amylin receptor complex on their surface.
Amylin is a neurochemical secreted by beta cells in the pancreas, and previous research has shown that it limits food intake.
“Researchers already know about this hormone, and for instance Novo Nordisk is working on a long-acting analogue of amylin to more effectively treat people with obesity. Novo Nordisk has already discovered that amylin analogues are a potentially very effective drug candidate against obesity, and using a data-driven approach we have identified the relevant types of cells in the brainstem and showed that they express the genes associated with developing obesity,” says Tune H. Pers.
Induced mice to eat less
In a further experiment, the researchers genetically modified the mice to enable the researchers to activate the cells in the brainstem that express amylin receptors.
The researchers found that activating these cells significantly reduced their food intake.
According to Tune H. Pers, this result emphasizes that this type of cell may be suitable as a target for treating people with obesity.
“We have shown that drugs can modulate these cells in mice so that they eat significantly less. Combined with our other results, this shows not only that these cells affect the development of obesity but also that we can influence this,” he says.
Unknown cells involved in developing obesity
The second and third types of cells, which Tune H. Pers and his colleagues identified as being important in the genetic component of developing obesity, express glucagon-like peptide 1 (GLP-1) receptors on the surface.
Researchers also already know about these cells, and GLP-1 receptor agonists are currently the most effective way of treating people with obesity using drugs. Novo Nordisk achieves this with semaglutide, and clinical trials have shown that this can help people with obesity to lose up to 20% of their body weight over 1 year.
“It is truly remarkable that our study shows that two of the four relevant types of cells in the brain express GLP-1 receptors, especially since the currently most effective drug treatment targets these receptors and cells,” explains Tune H. Pers.
However, researchers know nothing about the last type of cell that Tune H. Pers and colleagues identified in their study.
“No one seems to know their function. However, these cells may be an interesting candidate as a new target for drugs to combat obesity. This is potentially exciting, but further research needs to be carried out,” says Tune H. Pers.
Tune H. Pers and colleagues are obtaining permission to carry out similar experiments using postmortem brains from brain donors. This will help to identify which cells treatments for obesity should target.