Periasamy, Muthu , PhD
Sarcolipin controls metabolism and obesity by increasing energy expenditure
General Research Subject: Obesity
Focus: Integrated Physiology, Integrated Physiology\Muscle, Obesity, Obesity\Pathogenesis
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Obesity is a growing epidemic in developed countries throughout the world and is closely linked with the development of type 2 diabetes mellitus. Prevention and treatment of obesity is challenging due to limited effective treatment options. In this grant we propose studying a protein called Sarcolipin that we recently discovered to be important in heat generation, cold tolerance, and diet-induced obesity in mice. Sarcolipin acts to uncouple a calcium-transport pump in skeletal muscle, causing the pump to burn extra calories while not being able to transport calcium efficiently.
Our central hypothesis is that because obesity is the result of greater caloric consumption than caloric expenditure over time, increasing energy expenditure by increasing Sarcolipin is sufficient to prevent obesity. The principal objective of this proposal is to understand how levels of Sarcolipin are controlled in muscle and how Sarcolipin can be used to prevent obesity. To accomplish this objective, a combination of genetically modified mice, high fat diets, and drugs that target metabolic pathways will be used. These studies will not only increase our understanding of how Sarcolipin regulates muscle metabolism, but also provide needed details to establish Sarcolipin as a novel target for the development of therapies to increase energy expenditure and control obesity.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Obesity has been increasing at an alarming rate during the last decade and is a major contributor to Type II diabetes. While reducing caloric intake is the best primary line of defense against obesity, increasing energy expenditure in key metabolic organs, such as skeletal muscle, can be an effective strategy to control obesity. Skeletal muscle constitutes ~40% of our body mass and is a major consumer of metabolites including glucose and fatty acids. The focus of our research is to develop strategies to increase energy expenditure in muscle to control obesity. In our laboratory we have recently identified a novel molecule namely sarcolipin (SLN) which is abundantly found in skeletal muscles including human. SLN inhibits the Ca2+ ion transport ATPase (by uncoupling the pump from ion transport) in muscle, causing the muscle to utilize more energy (ATP) to perform normal Ca2+ transport. By this mechanism, SLN increases energy cost and at the same time produces more heat in muscle.
We found that this protein, SLN, is critical for temperature maintenance (heat generation) and loss of SLN (gene deletion) resulted in poor cold tolerance and mice were unable to survive in cold. Interestingly, loss of SLN also predisposed mice to develop obesity, but increased levels of this protein protected mice from high fat diet induced obesity and diabetes. These studies support the hypothesis that SLN can increase energy expenditure and prevent obesity. Moreover, these studies suggest that increasing energy expenditure in muscle could be used as an effective strategy to prevent obesity in mammals including humans. Our sincere hope is that this research will lead to an understanding of how SLN promotes increased energy expenditure in muscle and ultimately developing agents that mimic SLN function... Because muscle is a large consumer of glucose; improved muscle metabolism will promote better utilization of metabolites and effectively prevent obesity and the development of Type II diabetes.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Our research will develop strategies to increase energy expenditure in muscle so that we could prevent obesity in human. To accomplish this we have identified a novel protein that increases calorie utilization upon increased consumption of food .
Our research will identify new therapies to increase energy expenditure and control obesity and diabetes risk.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
It is important for me personally to become involved in diabetes research because it affects several people close to me, including myself. In addition, an enormous and growing number of people from my country of birth, India, as well as my country of citizenship, the United States of America, are currently struggling with the many clinical complications of diabetes. For many years I have been researching the biochemistry and physiology of healthy and diseased muscle. This award will allow us the financial freedom to thoroughly apply our expertise in studying muscle to an area of much need -- diabetes.
In what direction do you see the future of diabetes research going?
The future of diabetes research is very bright. Many excellent scientific tools from a variety of fields are becoming widely available to probe the intricate pathways controlling metabolism. Due to our rapidly developing understanding of the connections between cell signaling and metabolism, I foresee that an increasing number of rationally designed and mechanistically-targeted pharmaceutical interventions will be developed in the next two decades that will greatly improve our control obesity and prevent the progression of diabetes.
In addition to these pharmaceutical improvements, I believe that research will also lead to a drastic improvement in support programs and technologies for diabetics to facilitate consistent long-term compliance with the interventions that have and will be discovered to prevent and control diabetes.
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