Wellen, Kathryn Elaine, PhD
Metabolic regulation of histone acetylation in adipocytes
General Research Subject: Type 2 Diabetes
Focus: Adipocytes, Insulin Action, Insulin Action\Metabolism, Insulin Action\Signal Transduction
Type of Grant: Junior Faculty
Project Start Date: July 1, 2012
Project End Date: June 30, 2015
Fat cells, or adipocytes, play a key role in the regulation of systemic metabolic homeostasis. Normal adipocyte function is often impaired in obesity, and this can contribute to the development of diabetes. Regulation of gene expression in adipocytes plays an important role in modulating their function. One element involved in regulation of gene expression is modification of nearby histones (proteins around which DNA is wrapped). Acetylation is one such modification and is generally associated with the activation of gene expression; thus, increased acetylation near a particular gene promotes its expression. Changes in nutrient availability can modulate histone acetylation through the action of an enzyme called ATP-citrate lyase (ACL).
The proposed research will investigate whether histones near genes of interest are specifically regulated in a nutrient-responsive manner. Additionally, it is known that additional proteins call acetyltransferases are necessary to mediate the effects of ACL on histone acetylation, and the identity of these proteins will be investigated in order to define a clear mechanism through which ACL regulates histone acetylation. Finally, the proposed work will investigate how insulin-regulated signaling pathways control the activity of ACL and its ability to modulate histone acetylation levels and gene expression in adipocytes. These studies should provide novel insight into mechanisms underlying metabolic diseases and could potentially suggest novel therapeutic targets.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My research focuses on the biology of adipocytes, or fat cells. Adipocytes are now recognized to be far more than simply storage depots for lipids and in fact play a key role in modulating whole body metabolic homeostasis. Normal adipocyte function is often impaired in obesity, and this can contribute to the development of diabetes. Hence, improving our understanding of the biology of adipocytes promises to lead to development of improved therapies for diabetes.
Specifically, our work seeks to elucidate the links between dysregulated metabolism in adipocytes and altered gene expression patterns. Regulation of gene expression in adipocytes plays an important role in modulating their function. One element involved in regulation of gene expression is modification of nearby histones (proteins around which DNA is wrapped). Acetylation is one such modification that is generally associated with the activation of gene expression; thus, increased histone acetylation near a particular gene is associated with its activation. Our work has shown that changes in nutrient availability can modulate histone acetylation levels through the action of an enzyme called ATP-citrate lyase (ACL). Our current goals are to elucidate the molecular links between altered cellular metabolism and changes in the epigenome in adipocytes and to define the physiological significance of this relationship. We anticipate that our work will provide novel insight into the molecular mechanisms that contribute to the development of diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetes research is conducted at multiple levels from uncovering the basic biological mechanisms underlying the disease, to studies of physiology, to development of new therapies and clinical trials. Each of these is crucial, and I believe that in order to develop better diabetes therapeutics, it is critical to understand the basic molecular mechanisms that underlie metabolic dysfunction. We have uncovered a novel pathway that links changes in cellular metabolism to the regulation of the genome. The functional implications of this link are not yet clear; however, it is likely to contribute to altered gene expression patterns in the metabolic tissues of diabetic patients, impacting the function of those tissues. We hope that better understanding of the links between altered metabolism and gene expression will pave the way towards development of novel therapeutic strategies.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes touches on all of our lives. Type II diabetes is becoming increasingly common in the US and around the world, and most people have friends or family members with diabetes. Its incidence is growing in children as well as adults, and the disease is a clear threat to the public health of current and future generations. My research is motivated by the need for better therapies for this disease and the hope that our research will provide novel insights that will point the way towards this goal. As a young scientist, receiving support from the American Diabetes Association will provide a critical boost to my laboratory’s research program. This award will play a major role in enabling my laboratory to pursue our research goals and in accelerating the pace of our progress.
In what direction do you see the future of diabetes research going?
Diabetes research will become more and more interdisciplinary. Novel breakthroughs are likely to come through research that explores the interface between different fields. Interactions between scientists specializing in distinct areas will allow integration of expertise and facilitate innovative approaches to the study of metabolic disorders.
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