Guertin, David A., PhD
Mechanistic target of rapamycin complex 2 pathways in brown fat growth and regulation
General Research Subject: Obesity
Focus: Adipocytes, Insulin Action\Signal Transduction, Insulin Action\Transgenic Models
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Obesity is a major risk factor for type 2 diabetes, dyslipidaemias, cardiovascular disease, and cancer. Obesity can result when energy intake exceeds energy expenditure. Unfortunately, simply reducing calorie intake or increasing physical activity may not be enough to reverse current trends leading to the exploration of alternative therapies. One alternate strategy is to develop a means of increasing cellular energy expenditure. A tissue that may be a particularly suitable target for such a therapy is brown fat. This interesting tissue specializes in burning lipid—rather than storing it like white fat--to generate heat.
Brown fat, which evolved for thermoregulation and is critical in small rodents and newborns, was recently shown to exist in significant quantity in adult humans. The presence of brown fat in adults raises the possibility that stimulating the growth or energy expenditure of this tissue could be a means to combat obesity; however to achieve this, a much deeper understand of the regulatory mechanisms controlling its development and function is required. This proposal investigates a possible mechanism of increasing brown fat activity that could have therapeutic potential as a strategy to increase thermogenesis.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
This project focuses on understanding the mechanisms that control the development and function of brown adipose tissue. Unlike white adipose tissue, which is the major site of energy storage, brown adipose tissue is specialized to expend energy to generate heat (a process called adaptive thermogenesis) Because brown fat expends energy when stimulated, it may be possible to stimulate brown fat growth and/or activity as a therapeutic strategy to combat obesity, which is often a precursor to more serious medical complications such as type 2 diabetes, cardiovascular disease, and even cancer.
We have identified a pathway in mice that appears to regulate energy expenditure in fat. We are investigating the mechanism behind this regulation and the potential for targeting this pathway in both brown fat and white fat to combat metabolic disorders.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our work focuses on a network of signaling molecules central to both cellular and whole-body glucose regulation and energy balance; therefore, all diabetics will benefit from a better understanding of this network. In this project, we are focusing in particular on how this network can be manipulated in increase energy expenditure in fat. If we can figure out the molecular mechanisms that control energy expenditure in fat, we may be able to develop therapies that can stimulate it in people. Such a therapy could be useful in countering obesity, which is a leading cause of type 2 diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
Personally, I am very interested in the evolution of metabolic regulation and how mammals have evolved an amazing capacity to store huge amounts of energy as lipid, and expend it from certain adipose tissues upon stimulation. The down side is that most people's modern diets are so diverged from our ancestral diets and rich in calories that the adaptations that allowed us to store and regulate energy balance are now leading to obesity and its associated complications.
From a research perspective, understanding the biology of adipose tissue and energy homeostasis is fascinating; but from a clinical perspective, understanding how to deal with an obesity epidemic and its complications like T2D is a major challenge of our time. As a junior laboratory in a very difficult time for funding, this research grant is critical to my lab's growth and success. Thank you.
In what direction do you see the future of diabetes research going?
Type 2 diabetes is the most common form of diabetes, and it is a complex problem. As such it will take a multidisciplinary approach to deal with it. As much as T2D is a medical problem, it is also a lifestyle and political problem in many cases. Ongoing basic research into the molecular basis of energy homeostasis in mammals is critical to understanding why diabetes occurs and how we can cope with it clinically. Because the problem of obesity is epidemic, and the drive to find new drugs is strong, I see T2D diabetes research focusing to a large extent on finding pathways or small molecules that can be targeted or used respectively to treat diabetes or to combat obesity.
Recent developments in cell based therapies suggest these approaches could also have clinical value and will be another research topic of future interest. However, I think it is important for people to be proactive in making good lifestyle decisions (for themselves and for their children), which would also have dramatic impact on diabetes and health span for many individuals. Therefore, I envision research into better ways to educate and encourage healthier lifestyles factoring heavily into the fight against diabetes.
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