Dr. Arany and his team at the Pennsylvania School of Medicine discovered a cellular signaling pathway that may be utilized for the treatment of obesity and diabetes. Their findings were published online ahead of print in Genes and Development.
White fat, which is a predominant form of fat found in adults, has several functions. It serves as a thermal insulator, keeping us warm. It cushions our organs and to some extent protects us from physical damage (imagine falling on your behind with no fat to take the hit). It is also involved in the endocrine signaling. However, the major function, which is most commonly thought of, is the storage of all those extra calories we ate, but did not burn. A large amount of white adipose tissue is associated with increased risk of metabolic disorders, such as obesity, cardiovascular diseases, and diabetes.
In contrast, brown fat, also known as “baby fat” is found mostly in babies, as well as in small amounts in the neck and upper back in adults. This type of fat tissue looks brown because it contains a large number of blood vessels as well as a high number of mitochondria. Mitochondria are little powerhouses of the cell, which burn energy by converting it into heat. Brown fat is therefore considered “healthy” tissue, since it burns calories, instead of storing them. Moreover, increased amounts of brown fat lead to better health outcomes. This has led researchers of a new study to ponder at some ways to boost the amount brown fat, while minimizing the white fat.
Dr. Arany’s team performed a series of elegant experiments in mice, identifying and successfully triggering one cellular pathway to turn white fat brown. The pathway involves the protein called FLCN. In concert with a signaling complex mTOR, FLCN normally keeps the white fat tissue white. FLCN-mTOR interaction in the white adipocytes inhibits the browning of the fat by blocking another protein, TFE3, from entering the nucleus of the cell. In mice whose FLCN gene was knocked out, this inhibition was relieved, allowing TFE3 to enter the nucleus and activate a key player of metabolism, PGC-1β. This protein, in turn, influenced the expression of various genes, ultimately leading to the browning of the white fat tissue.
Adipocytes with the altered FLCN gene exhibited several characteristics of the brown fat tissue. They became visibly browner, as they accumulated more mitochondria. Their mitochondria became more efficient at utilizing oxygen for energy burning. Finally, the expression pattern of specific genes became more like that of the brown adipose tissue.
To confirm the results, the researchers approached the signaling cascade from the other end – they induced overexpression of PGC-1β, which also activated the browning effect in white fat cells.
These findings are exciting as they point to a cascade of proteins that could potentially be used as therapeutic targets. If there is a drug that promotes PGC-1β activity and turns the white fat brown, we could have another weapon in our arsenal to fight the growing health problems of obesity and diabetes.
Written By: Valeriya Laskova, MSc