Floyd, Elizabeth , PhD
Regulation of PPARgamma activity by the ubiquitin system
General Research Subject: Obesity
Focus: Adipocytes, Insulin Action\Signal Transduction, Obesity\Animal Models
Type of Grant: Basic Science
Project Start Date: July 1, 2010
Project End Date: June 30, 2013
Diabetes Type: Type 2 diabetes
As obesity has become more prevalent in the United States, the number of persons diagnosed with type 2 diabetes has also increased. The strong correlation between obesity and developing type 2 diabetes points to the importance of understanding how fat cells are formed and maintained. The principle investigator is interested in understanding how the biochemical processes that are responsible for determining protein stability affect the formation and expansion of fat cells. In particular, the laboratory is focused on studying the ubiquitin proteasome system, a highly conserved pathway that is responsible for the carefully timed destruction of most cellular proteins.
This proposal investigates how the ubiquitin proteasome system controls the activity of a protein called PPARgamma, the 'master switch' in forming fat cells. The controlled destruction of the PPARgamma protein by the ubiquitin system plays a role in determining PPARgamma activity. Understanding the basic interactions between the ubiquitin proteasome system and PPARgamma could help with the treatment of type 2 diabetes by describing potentially new targets for drug development that are aimed at modulating PPARgamma protein levels.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Obesity is a strong predictor for developing insulin resistance and type 2 diabetes. Accumulation of excess adipose tissue depends on a protein in fat cells called the peroxisome proliferator activated receptor gamma or PPAR . PPAR functions at the crossroads of lipid and glucose metabolism, regulating the production of other proteins needed for lipid and carbohydrate metabolism in adipocytes. PPAR is also the cellular target of a commonly prescribed class of anti-diabetic drugs, the thiazolidinediones (TZDs). These drugs alter PPAR activity and stability, an indication that understanding the link between PPAR activity and stability may offer new insights into how obesity contributes to insulin resistance and type 2 diabetes. The stability of PPAR is determined by the ubiquitin-proteasome system, a highly conserved pathway that is responsible for the carefully timed degradation of proteins, making this pathway central to cellular functions. Our studies show that PPAR activity is also regulated by the ubiquitin proteasome system in adipocytes.
To understand how this system of enzymes regulates PPAR activity and stability, we focused on the components that are known to interact directly with targeted proteins such as PPAR the ubiquitin ligases. Using a novel screening method based on RNA interference technology, we identified a small set of ubiquitin ligases that affect PPAR protein levels in adipocytes. This project is focused on one of the ligases, a protein called Siah2. In addition to regulating PPAR protein levels, Siah2 also affects insulin sensitivity in adipocytes, linking regulation of PPAR stability by the ubiquitin system to control of insulin sensitivity. In this project, we will take a closer look at how Siah2 regulates PPAR stability and determine if the effect of Siah2 on PPAR stability is related to controlling PPAR activity in adipocytes. In addition, we will investigate the effect of diet and obesity on the regulation of Siah2 itself in adipose tissue and how this correlates with changes in PPAR stability and activity. As evidence accumulates that modulation of PPAR levels, rather than a simple 'on-off' model, can profoundly affect PPAR activity, these studies may describe new therapeutic targets for the treatment of insulin resistance and type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The anti-diabetic thiazolidinediones (TZDs) work by activating PPAR in adipocytes. These drugs are very effective at improving insulin sensitivity but have serious side effects, including bone loss. We know that TZD activation of PPAR in adipocytes also destabilizes PPAR protein by increasing the interaction of PPAR with a system of enzymes called the ubiquitin proteasome system. By learning more about how this system of enzymes is related to PPAR activation, we will better understand how TZDs work to control insulin sensitivity. This basic knowledge could lead to new insights into why TZD treatment is accompanied by serious side effects and offer an alternative way to target PPAR in treating type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Before returning to graduate school, I worked for several years as a critical care nurse. Every day at work, I saw the health problems associated with diabetes. And like many other people, members of my own family have had type 2 diabetes. The prevalence of diabetes and the serious consequences of the disease make understanding the basic molecular and physiological problems underlying the development of diabetes an important area of research. I am studying a pathway (the ubiquitin proteasome system) that was first described in the early 1980s, yet very little is known about how the ubiquitin proteasome system functions in adipocytes or what role it plays in insulin resistance and type 2 diabetes. This award will allow me to continue studying how PPAR , a pivotal protein in adipocyte biology and glucose metabolism, is regulated by the ubiquitin proteasome system in adipocytes. These studies may lead to new insights into the molecular interactions that contribute to the development of diabetes and I am grateful to the American Diabetes Association for this opportunity.
In what direction do you see the future of diabetes research going?
A wealth of information is available from large-scale genomic, transcriptomic, proteomic, and metabolomic-based studies. These technologies are making an unprecedented amount of information available on every aspect of diabetes, ranging from genetic origins of the disease to basic molecular interactions in multiple cell types. The interesting challenge will be developing bioinfomatic tools with the sophistication to fully 'mine' this treasure-trove of data.
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