New research by researchers at the Scripps Research Institute and the collaboration of institutions identified a key regulator of fat cell development which can be a target for drugs for obesity and diabetes.
In an article published in the latest issue of cell metabolism, scientists describe a protein called TLE3 which acts as a double-switch to activate the signals that stimulate the formation of fat cells and those fat cells from developing countries. TLE3 works in partnership with a protein that is already the target of several drugs for diabetes, but its use has been affected by serious side effects.
"There is definitely a need for targets of the alternative drug" said Scripps Research Professor Enrique Saez, who led the study with Professor Peter Tontonoz, of the Howard Hughes Medical Institute and the University of California at Los Angeles (UCLA). "Our goal is to understand how fat cells form so we can develop better treatments for obesity and related disorders".
FAT: the good and evil
In the culture of today, fat has a bad reputation, but it is not justified. Adipose tissue (FAT) stores excessive fat, called lipids, obtained from the diet so that they accumulate in other tissues such as the liver and muscles, which may cause damage. Adipose tissue also produces hormones that help control the balance of insulin in the blood and regulate energy production and consumption.
But, in certain circumstances, as in obesity, adipose tissue no longer works as it should. "When we have too much fat, it tends to be dysfunctional," said Saez. "It's that time of the execution in problems such as resistance to insulin and diabetes".
One way to combat this kind of problem is generating cells of fat for additional health and improve the functioning of existing ones.
Make more fat cells
As with all the cells of the body, fat or fat cells come from stem cells, which are induced to differentiate into fat to completely mature cells to transmit signals of a molecule to the next route.
The activity of a protein called receptor peroxisome range apply enabled (or PPAR for short) plays a central role in the paths necessary to form fat cells and activation of its function. "PPAR is interesting because it is itself activated by lipid," said Saez. "When excess lipids are present in the body, fat activates the PPAR so that it stimulates the formation of fat cells to more deal with these lipids.".
On the other hand, another way, regulated by a family called Wnt protein blocks Adipocyte differentiation, so it must be disabled to fat cells to the form.
A dual regulator of differentiation
To find more players in the formation of the adipocytes, Saez, Tontonoz and his colleagues induced cells to grow in a dish to differentiate into adipocytes. Scientists then individually tested the possibility of 18 000 genes to increase conversion of adipocytes to undifferentiated cells that are fully functional, the search for genes that may play a role in this process.
In this way, they have identified a gene coding for the protein TLE3, which had never been linked to the development of fat.
Saez, Tontonoz and his colleagues have discovered that PPAR becomes a TLE3 product. Then, TLE3, forms a complex with PPAR and allows other genes the paths necessary to the formation of the adipocytes.
In addition, TLE3 disables Wnt signaling "how close do we want Wnt to enable differentiation to occur," said Saez. "TLE3 has a dual function: it is a positive regulator for PPAR and a negative regulator for Wnt.".
New diabetes drug targets
A class of drugs introduced in the 1990s to treat diabetes, thiazolidinediones, is stimulating the PPAR activity. But these drugs are far from optimal. One of these, rosiglitazone (Avandia), was recently published on restrictions in the United States and is in the form of withdrawal from the market in Europe due to increased cardiovascular risk. It is believed that they are the side effects of thiazolidinediones due to activation of PPAR in the adipose tissue.
To verify if the TLE3 could provide an alternative destination for medications for diabetes, Saez and Tontonoz engineered mice that produce human adipose tissue TLE3 in normal quantities, and then feeding mice a diet high in fat. Normally, this type of diet produces resistance to insulin and glucose regulation changes, risk factors for diabetes. But engineered mice are more sensitive to insulin and had better glucose metabolism than regular mice fed with high fat diet.
"These are the same results you will get if stimulating the PPAR," said Saez. "So in theory it could improve the TLE3 activity to improve the function of adipose tissue and improve symptoms of diabetes."
The first author of the book is j. Claudio Villanueva of Howard Hughes Medical Institute. In addition to Saez, Tontonoz, and Villanueva, co-authors of the book include Hironori Waki, Kevin Wroblewski, Rimer Boyadjian, and Lily c. Chao of Howard Hughes Medical Institute; Cristina Godio and Wen-Ling Chou Scripps Research; Andrea Hevener of UCLA. Ronni Nielsen and Susanne Mandrup at the University of the South of the Denmark. and Leo Vargas and Schmedt Christian of the Institute of Genomics of the Novartis Research Foundation.
This research was funded by the national institutes of health, Howard Hughes Medical Institute, the American Diabetes Association and McDonald's Center for type 2 diabetes and obesity.
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