In recent years, research has been showing the many negative effects that fat and obesity can have in the brain on top of the known effects that fat can have on the rest of the body. For example, obesity has been linked to white matter deficits, which can lead to language, memory, and visual problems, as well as diseases like Alzheimer’s, dementia, and depression.
Researchers are working on understanding the mechanism by which obesity causes problems in the brain. From this, they will hopefully be able to develop new treatments for obesity through targets in the brain. If we could treat obesity outside of the brain, though, we could prevent any negative effects it would have on the brain.
A group of researchers from the University of Pennsylvania decided to take this direct approach to treating obesity. They decided to try to turn white fat into brown fat instead of targeting the proteins or mechanisms in the brain that obesity effects in the brain. They have recently discovered a way to successfully make this conversion by targeting a gene in fat cells.
Before moving on, though, isn’t fat just fat? What is the difference between white and brown fat and why should we care?
When we think of fat, we typically are thinking of white fat, which is involved in the storage of energy in our bodies as triglycerides. It can also produce hormones such as adiponectin, which is involved in making the liver and muscle less sensitive to insulin and is thought to make people less susceptible to diabetes and heart disease. White fat is more plentiful that brown fat, especially in overweight people, and when white fat is in excess it slows or stops producing adiponectin and can have adverse effects on many parts of the body.
Brown fat on the other hand, is thought to be “good fat.” When brown fat cells are stimulated, they are responsible for burning calories through the production of heat. Children and lean people tend to have more brown fat than white fat, and stimulating brown fat keeps people warm and burns white fat. The burning of white fat can prevent diseases such as diabetes, so the discovery at Penn University could be very significant and lead to future treatments of obesity.
The researchers discovered a gene that can start a “browning process” in white fat cells when it is deleted. The protein produced by this gene is called foliculin, or FLCN. It is a known tumor suppressor, and is key for preventing the conversion of white fat into brown.
When FLCN is removed, a protein known as TFE3 can be transported into the nucleus of white fat cells. This is usually prevented by FLCN and another protein, mTOR. Once in the nucleus TFE3 binds to DNA and activates a protein called PGC-1β, which is involved in cell metabolism regulation. After PGC-1β activation a set of genes were transcribed that began the browning of white fat cells. This process is simplistically outlined in the figure below.
This browning process was shown to occur the white fat of mice after the deletion of the FLCN gene, and one of the reasons for this is that the fat cells started producing more mitochondria. These are cellular organelles that are responsible for the production of chemical energy in cells and are responsible for the added heat production in brown fat cells. On top of producing more mitochondria in white fat cells, the deletion of the FLCN gene changed the structure of white fat cells, increased the activity of mitochondria that were present, and changed gene expression.
Although this pathway is not well understood at this point, it is possible that it could be targeted to treat obesity and the diseases that stem from it by converting white fat into brown. Although this treatment wouldn’t directly act on the brain, it could prevent the negative effects that obesity has been found to have on the brain.
Future Strategy to Treat Obesity and Prevent Damage in the Brain
