Collins, Sheila , PhD
Adipocyte 'browning' and body fat reduction by cardiac natriuretic peptides
General Research Subject: Obesity
Focus: Adipocytes, Exercise\Regulation of Muscle Metabolism, Obesity\Animal Models
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Obesity is an epidemic in the US with annual costs exceeding $100 billion/yr, making it a public health and economic crisis. Lifestyle and behavioral approaches have modest and transient effect while approved therapies targeting appetite or fat absorption have poor tolerability or safety concerns. Drugs that act by increasing energy expenditure would be valuable.
We recently discovered that the heart hormones ANP and BNP best known for their regulation of blood pressure can cause energy-storing fat cells to take on characteristics of so-called 'brown fat cells'. These cells are able to consume calories because they contain a specialized protein called 'uncoupling protein'. The ability of ANP and BNP to promote this 'browning' of fat cells depends upon the relative levels of two 'receptors' that they interact with on cells: one called NPRA promotes the signals for 'browning' while the other called NPRC sweeps up ANP and BNP and removes them from circulation. In this project we will test the idea that when levels of the NPRC protein are eliminated from fat cells in an animal, the 'browning' of the fat cells will burn excess calories and protect the animal from diet-induced obesity. We will also test the possibility that the skeletal muscles also respond to ANP and BNP to also increase calorie burning. We will use mice that lack the NPRC or not for these diet studies and we will also culture the muscle and fat cells to specifically understand their responses to ANP and BNP.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating, and curing diabetes?
The research in our lab examines how calories from food are either stored in the body as fat or stimulated to be consumed in order to reduce body fat and avoid the complications of obesity -- such as type 2 diabetes. We are examining the similarities and differences between white fat cells -- the storage form of fat -- vs. a type of fat cells called a 'brown' fat cell, which can consume calories by a process called non-shivering thermogenesis. These brown fat cells can 'burn' calories without doing any useful work for the cell except to generate some heat. In so doing these cells have the potential to be able to prevent obesity.
The main hormone known to stimulate these brown fat cells is the adrenaline system. Our recent work has discovered that hormones made in the heart, called 'cardiac natriuretic peptides' (NPs), are able to increase fat cell metabolism and brown fat in a manner similar to the adrenaline system. The NPs are known to reduce blood pressure. We show that NPs can work together with the adrenaline system to increase fat oxidation, thereby potentiating the effects of both. By increasing the amounts of these peptides and their ability to activate the fat cell we show it is possible to reduce body fat and protect against insulin resistance. In addition to the actions of the NPs in fat, our recent unpublished findings show that they also are able to increase calorie burning in skeletal muscle. By understanding the biochemical mechanisms by which these NPs drive fat and muscle metabolism we have the potential to reduce the risk of obesity, the associated insulin resistance leading to type 2 diabetes, with an added benefit of maintaining a lower blood pressure.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
One of the biggest driving factors in the development of insulin resistance and progression to Type 2 diabetes is being obese. The ready access to food with minimal energy expenditure in order to obtain it clashes with the evolutionary needs developed over millennia to preserve calories at all costs since the ability to obtain food was energy-demanding as well as rare. We must find ways to both manage food intake as well as increase energy expenditure by all means necessary. However, to date strategies to reduce appetite and to increase voluntary energy expenditure have made little impact on the prevalence of obesity and diabetes. One's basal metabolic rate is a significant fraction of energy expenditure. Thus if we could increase this rate by even a small percentage per day we could reduce weight gain and its complications.
By understanding how the adrenaline system together with the heart-derived natriuretic peptides (NPs) can increase both the numbers and activity of energy-burning brown fat cells, as well as increase calorie burning in skeletal muscle, independent of physical activity or reduced food intake, we hope to be able to find safe and effective therapies for subjects that are at risk for weight gain and thus reduce or prevent the development of insulin resistance and its eventual progression to frank type 2 diabetes requiring insulin injection as a last resort therapy.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
It is crystal clear that the biggest -- and fastest accelerating -- risk to human health globally is obesity and it's closely accompanied devastating complication: diabetes. In addition to the reduced quality of life, physical limitations and increased mortality, obesity and its complications are taking an inappropriately enormous financial toll on the US and many other nations. Of great alarm to me personally is the rapidly escalating rate of obesity and complications such as type 2 diabetes in children. Since children of obese and insulin resistant parents frequently develop these conditions themselves, not only because of lifestyle but because of evidence that there are inherited 'epigenetic' changes, reducing obesity and metabolic disease in parents might be a strong protector against this scourge of metabolic disease in children. This award is providing us the chance to test the idea that the beneficial effects of the blood pressure reducing 'cardiac natriuretic peptides' in fact have equally powerful effects on fat and muscle metabolism. We will learn a great deal about how these peptides regulate this metabolic process as well as how the cell senses and responds biochemically to them.
In what direction do you see the future of diabetes research going?
Greater emphasis on understanding how to increase metabolic rate in individuals as a way to resistant weight gain to the point of frank obesity and its associated metabolic complications, the most insidious being insulin resistance.
I believe that the field will move away from trying to find solely appetite reducing solutions to obesity, to embrace efforts to target fat and muscle metabolism. I also believe that the role of stem cell research to find replacement insulin-producing beta-cells will continue and with it, the potential for stem cells to be programmed to be energy-consuming brown fat cells.
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