Rader, Daniel J., MD
The role of ARV1 in adipose biology, obesity, and type 2 diabetes
General Research Subject: Obesity
Focus: Adipocytes, Integrated Physiology, Integrated Physiology\Fatty Acid Metabolism, Obesity, Obesity\Animal Models
Type of Grant: Minority Undergraduate Internship
Project Start Date: January 1, 2013
Project End Date: December 31, 2013
ARV1 is a novel gene that is involved in the metabolism of lipids in cells, including adipocytes, the major cell type in adipose tissue. We found that when the ARV1 gene was deleted in mice, the mice had substantially less adipose tissue and improved glucose tolerance. We replicated these findings when we specifically deleted the gene in adipose cells. Our goal is to understand how ARV1 influences the development of adipose tissue and the ability of the body to metabolize glucose. A greater understanding of this mechanism could lead to better ways to prevent obesity and type 2 diabetes.
Mentor: Daniel J. Rader Undergrdaute: Mikhaila Smith
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
Our project is focused on the interaction between lipid/cholesterol disorders and diabetes. Diabetes and obesity are growing health epidemics in the United States and developed countries around the world. Excessive deposition of fat in adipose tissue plays a critical role in the pathogenesis of these diseases. On the other side of the spectrum, individuals exist with lipodystrophies - a series of conditions where fat is not stored properly in adipose tissue and gets deposited in the liver, muscle and other organs. Individuals with lipodystrophy also tend to be insulin resistant, and there is a great need for mouse models to understand and treat these conditions.
We generated mice genetically engineered to lack the ARV1 gene in the adipose tissue. Results obtained from these mice indicates that ARV1 is a critical determinant of fat mass, as well as the body's response to glucose. These mice have a major lipodystrophic phenotype (having fat in the wrong places). In contrast to human lipodystrophies, we have found that these mice are actually more glucose tolerant and insulin sensitive (in other words, protected from diabetes). Because of this, these mice can provide us with valuable information about how adipose (fat) tissue works to affect glucose metabolism. These may hold valuable clues for the treatment of lipodystrophy in humans. Conversely, information gained from these studies will also be useful in determining how an individual's genes affect their predisposition to obesity and diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Diabetes is a group of diseases that lead to high blood glucose levels due to defects in either insulin secretion or insulin action in the body. Our current understanding is both genetics and environmental causes such as obesity and lack of exercise appear to play roles. Although much has been learned about the mechanism of diabetes, the role of fat tissue in insulin sensitivity and development of diabetes is not clear. Fat tissue is a complex metabolic and endocrine organ.
In our current project we intend to discover why people with lipid disorders are predisposed to diabetes. We have generated a new mouse model which has a deficiency in lipid metabolism in fat. We hypothesize that lipid accumulation inside the fat cells will lead to inflammation and cell stress, which pose a threat to normal cell functions including lipid storage and secretion of various factors which are involved in insulin sensitivity. Lipid abnormalities in fat tissue eventually lead to insulin resistance and type 2 diabetes. Our study will allow us to relate abnormal glucose metabolism to the underlying proteins and genes in fat tissue we are studying. In other words, we will study the potential clue to the link between fat and diabetes. Ultimately, our goal is to find out better treatment and prevention against lipid disorders and diabetes
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Diabetes and obesity are growing health epidemics in the United States and developed countries around the world. As a clinician practicing Preventive Cardiology, I frequently treat patients exhibiting metabolic syndrome, a group of conditions occurring together that increase the risk of heart disease, stroke and diabetes. Our current understanding is that both genetics and environmental causes such as obesity and lack of exercise appear to play roles.
My research is focused on genetic/molecular regulation of lipid and lipoprotein metabolism related to the mechanisms of metabolic diseases including diabetes. This Minority Undergraduate Internship Award will support the effort of undergraduate student Mikhaila Smith in our ongoing studies designed to elucidate the role of the ARV1 gene in lipid metabolism and glucose homeostasis.
In what direction do you see the future of diabetes research going?
Metabolic Syndrome (Syndrome X) has been defined as a cluster of at least 3 of 5 criteria: insulin resistance and glucose intolerance, obesity, high blood pressure, low HDL (high-density lipoprotein, good cholesterol) cholesterol, and high triglycerides. Alterations in plasma lipid levels such as high cholesterol and fatty acids are risk factors to the various metabolic diseases including atherosclerosis, stroke, obesity and insulin resistance.
Our lab is working to delineate molecular regulation of lipid and lipoprotein metabolism related to the mechanisms of various metabolic diseases including diabetes. All the above factors are intercalated and contribute to the development of these diseases. Therefore, studies on gene-gene and gene-environment interactions would provide us invaluable evidence to better understand the mechanism of these diseases and devise new prevention and treatment approaches for diabetes.
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