A new target for obesity and diabetes drugs
A new hope for diabetic and obese patients: the "double switch" of fat cell formation has been openedNanoNewsNet based on the materials of the Scripps Research Institute:
Team Finds Dual Switch Regulates Fat Cell Formation
Scientists at the Scripps Research Institute have discovered a key regulator of fat cell formation. This protein molecule may become the target of more effective drugs for the treatment of obesity and diabetes.
In an article published in the latest issue of the journal Cell Metabolism (TLE3 is a dual-function transcriptional coregulator of adipogenesis), scientists described the protein TLE3, which is a double molecular "switch" that turns on signals that stimulate the formation of fat cells and turns off signaling pathways that prevent adipogenesis. The TLE3 protein works "in tandem" with another protein that is already the target of several antidiabetic drugs. However, the use of these drugs is limited by serious side effects.
"Of course, there is a need for alternative targets," says Enrique Saez, a researcher at the Scripps Institution, who led this study together with Professor Peter Tontonoz from the Howard Hughes Medical Institute and the University of California, Los Angeles (University of California, Los Angeles). "Our goal is to understand how fat cells are formed, which will allow us to develop more effective drugs for the treatment of obesity and related diseases."
In modern culture, fat has a bad reputation, but this is not entirely justified. Adipose tissue accumulates excess fats, or lipids, obtained from food, preventing their accumulation in other tissues, for example, in the liver or muscles, where they can harm the body. In addition, adipose tissue produces hormones that allow you to control the balance of insulin in the blood and regulate the synthesis and use of energy. But in some conditions, such as obesity, it stops functioning properly.
"When we have too much fat, its functions are disrupted," explains Saez. "Then we face problems like insulin resistance and diabetes."
One of the ways to solve these problems is the formation of new fat cells and strengthening the function of existing ones. Like all cells in the body, fat cells, or adipocytes, are formed from stem cells. Stem cells differentiate into mature adipocytes, obeying a cascade of signals transmitted along molecular chains.
A central role in the stimulation of signaling pathways necessary for the formation and functioning of adipocytes is played by the activity of a protein called the peroxisome proliferator-activated receptor gamma (PPARy).
"PPAR-gamma is interesting because it is activated by fats itself," explains Saez. "Excessive amounts of lipids turn on PPAR-gamma and thus stimulate the formation of fat cells to solve problems associated with these same lipids."
But another signaling pathway regulated by Wnt family proteins blocks adipocyte differentiation, so in order for adipocyte formation to continue, it needs to be turned off.
To find helpers in the formation of adipocytes, Saez, Tontonoz and their colleagues forced cells growing in laboratory culture to differentiate into adipocytes. Then, to find genes that enhance the transformation of undifferentiated cells into fully functional adipocytes, the scientists tested the capabilities of each of the 18,000 genes that could play a role in this process.
Thus, they identified a gene encoding the protein TLE3, which has never been associated with the development of adipose tissue before.
Scientists have found that PPAR-gamma includes the synthesis of the protein TLE3. TLE3 then forms a complex with PPAR-gamma and helps it activate other genes and molecular pathways necessary for adipocyte formation. In addition, TLE3 disables the signaling pathway of Wnt proteins.
"This is how Wnt is turned off, activating the differentiation of stem cells into adipocytes," explains Saez. "TLE3 performs a double function: it is a positive regulator for PPAR–gamma and negative for Wnt."
Fat cells – adipocytes – are formed from mesenchymal stem cells. This process is regulated by several signaling pathways. The molecular pathway regulated by proteins of the Wnt family blocks the differentiation of adipocytes. The excess amount of lipids includes PPAR-gamma and thus stimulates the formation of fat cells. PPAR-gamma enables the synthesis of the TLE3 protein. TLE3 then forms a complex with PPAR-gamma and helps it activate other genes and molecular pathways necessary for adipocyte formation. In addition, TLE3 disables the signaling pathway of Wnt proteins. Thus, the TLE3 protein performs a double function: it is a positive regulator for PPAR-gamma and negative for Wnt. (Fig.: cell.com/cell-metabolism )
A class of drugs for the treatment of diabetes that appeared in the 90s, thiazolidinediones, stimulates the activity of PPAR-gamma. But these drugs are far from perfect. Recently, the sale of one of them, rosiglitazone (Avandia), was restricted in the United States and banned in Europe due to an increased risk of cardiovascular complications. It is believed that the side effects of thiazolidinediones are associated with the activation of PPAR-gamma not only in adipose, but also in other tissues.
To test whether the TLE3 protein could become an alternative target for antidiabetic drugs, Saez and Tontonoz created genetically engineered mice whose organisms produced an increased amount of human TLE3 in adipose tissue. These mice received food with a high fat content. As a rule, this amount of fat leads to the development of insulin resistance and changes in glucose metabolism. Both are a risk factor for diabetes. But the genetically engineered mice were more sensitive to insulin and showed better glucose metabolism than normal mice who also received excessive amounts of fat.
"These are the same results that we get if we stimulate PPAR-gamma," concludes Saez. "Thus, it is theoretically possible to enhance the activity of TLE3 and increase the function of adipose tissue formation, reducing the risk of diabetes."
Portal "Eternal youth" http://vechnayamolodost.ru13.04.2011