Geschatte leestijd: 4 minutenResearchers at the University of California – San Francisco have discovered a new function of beige fat that protects against obesity and diabetes.
Brown Fat and Beige Fat
When your body cools down, shivering of the muscles can be a way to generate heat. When the cold persists, the body takes other actions to generate additional heat. For example, it has been known for decades that specialized fat cells burn energy under the influence of cold temperatures to generate heat.
Initially, the existence of ‘brown fat’ was discovered. While ‘white fat’ is a form of energy storage, brown fat actually burns stored energy to generate heat. Babies have proportionally more brown fat as a defense against cold. Also, mammals in hibernation, such as some bears, have a lot of brown fat. However, in adult humans, this amount is considerably lower. Brown fat contains many mitochondria, the energy factories of cells. These contain a lot of iron, explaining the rust color. However, it has been known for about 20 years that under cold conditions, certain fat cells in normal adipose tissue behave like brown fat.
In 2012, it was determined that it is another type of fat that exhibits this behavior, ‘beige fat’ [1]. Beige fat is found within adipose tissue and can change its function from white fat to brown fat in response to cold. Subsequent studies demonstrated that mice with more brown fat were better protected against type 2 diabetes and obesity. By burning more calories for heat, the mice were better able to rid themselves of unhealthy amounts of white fat. However, the process by which this conversion of energy into heat is carried out was not fully known.
Fat Burning by UCP1
What the researchers already knew was the role and function of a protein called uncoupling protein 1 (UCP1). This protein is found only in brown and beige adipose tissue. UCP1 is located in the mitochondria of brown fat cells and provides an alternative route to generating energy (in the form of ATP) to produce heat. For this reason, it is also called ‘thermogenin’. The activity of UCP1 increases when it gets cold, but also when too much is eaten. Therefore, it is the best-known player in mammals for providing heat other than heat by shivering. However, there are some types of mammals known, such as pigs, that do not have functional UCP1. Yet they are able to regulate their heat in cold temperatures. The researchers at the Kajimura laboratory wondered how that could be without UCP1.
In previous studies, the researchers removed UCP1 from mice that still had a lot of brown and beige fat. Despite the lack of UCP1, the mice were still better protected against obesity and type 2 diabetes thanks to the amount of brown and beige adipose tissue. This surprised them because UCP1 had been the only known thermogenic protein for more than 20 years.
Could there then be a second way in which brown and beige fat cells are able to increase temperature?
New Thermogenic Proteins Discovered
The researchers found this alternative route and a pair of proteins responsible for it; SERCA2b and ryanodine receptor 2 (RyR2). An important discovery and not only as a missing piece of the puzzle. The way these proteins generate heat is very interesting as a possible means against obesity and type 2 diabetes. Their findings were published last week in Nature Medicine [2].
These proteins, with names that seem to come from Star Wars, are normally responsible for the availability of calcium in fat cells. When the amount of calcium is too high, SERCA2b can use energy to transport extra calcium to storage sites in the fat cell. When there is a shortage, RyR2 ensures that the calcium is released from the storage sites. However, the Kajimura team discovered that under cold conditions, both proteins are activated simultaneously. By comparison, you can think of pressing the gas pedal and the brake of a car at the same time with the sole purpose of generating heat in the engine. Instead of gasoline, it is glucose that is burned here.
So much glucose is burned in this process that lowering the activity of SERCA2b in mice affected blood sugar levels. This makes these proteins a potentially interesting player in the fight against diabetes. One of the usual suspects in diabetes is a prolonged elevated blood sugar.
Now that we’ve found that beige fat burns glucose using SERCA2b, it explains many things. This is why mice become diabetic when we reduce beige fat, but disrupting UCP1 does not cause diabetes, and this is why mice are protected from diabetes in the presence of more beige fat.
-Shingo Kajimura, University of California – San Francisco
Experiments with isolated fat cells from humans and pigs show that this action of SERCA2b applies not only to mice. However, it is not clear which process for generating heat is dominant, UPC1 or SERCA2b + RyR2.
That beige fat has multiple ways to generate heat does not seem strange from an evolutionary perspective. Regulating body temperature is so important that multiple mechanisms are needed, as evidenced by pigs that do not have functional UCP1.
Beige Fat Medication and/or Supplements
The researchers are particularly excited about the results because they point to the possibility of developing medication or even supplements to activate SERCA2b in beige fat. With this, they hope that blood sugar can be better regulated and the risk of obesity and type 2 diabetes reduced.
One example is ginger. It has long been known that eating ginger increases body temperature. However, exactly how this happens is unclear. There is evidence that the active ingredient in ginger, gingerol, activates SERCA proteins. With this, ginger and specifically gingerol are interesting players to further investigate their effect on activating beige fat and thus burning more calories.
References
- Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar M, Virtanen KA,Nuutila P, Schaart G, et al. 2012. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150: 366–376
- Kenji Ikeda, Qianqian Kang, Takeshi Yoneshiro, Joao Paulo Camporez, Hiroko Maki, Mayu Homma, Kosaku Shinoda, Yong Chen, Xiaodan Lu, Pema Maretich, Kazuki Tajima, Kolapo M Ajuwon, Tomoyoshi Soga, Shingo Kajimura. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nature Medicine, 2017; DOI: 10.1038/nm.4429
