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Interviewer: Turning unwanted white fat into good fat. We'll talk about that research next on The Scope.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Claudio Villanueva. He's assistant professor in the Department of Biochemistry and an investigator in the Center for Diabetes and Metabolism at the University of Utah. He was just awarded a grant from the National Institutes of Health to investigate fat biology with an eye towards developing innovative approaches to the obesity problem. Dr. Villanueva, your work is looking at differences between white fat and brown fat. I think a lot of people may not really know what brown fat is. Can you talk about that?

Dr. Villanueva: Sure. There are two different types of fat cells that are known as white and brown fat and the white fat is probably most known to people because the white fat cells can store lots of energy. When you consume excess calories that extra energy goes to your white fat cells and is stored at lipids. And over time these white fat cells increase in size and they also increase in number. They are the ones that you would sort of point to when you look at someone who is obese or overweight, they have lots of white fat. Brown fat on the other hand, its function is to generate heat to use that lipid and turn that chemical energy into heat. This process consumes a lot of energy.

Interviewer: So brown fat, is that something that you and I have normally?

Dr. Villanueva: Yes, adults have brown adipose tissue, some more than others. There is this correlation that obese individuals have less brown adipose tissue and individuals that are lean tend to have more. There's this correlation with obesity and diabetes as well where individuals that are protected against diabetes tend to have more brown fat.

Interviewer: So brown fat is kind of a good fat in a way.

Dr. Villanueva: That's right

Interviewer: Part of your project is to investigate how to convert white fat into brown fat, right? First of all why would you want to do that?

Dr. Villanueva: If we can turn on mechanisms that switches the balance from energy storage to energy expenditure this could be a therapeutic target to combat obesity. And there are these other types of fats cells called beige fat cells. They behave just like brown fat cells, they're thermogenic, they consume lots of energy, but typically they appear in the white adipose tissue or the white fat cells after prolonged cold exposure, so several days of cold exposure.

Interviewer: If your goal is to turn white fat cells into beige fat cells, I imagine first you need to do is understand what goes on within the cell in order to make that happen. What do we know about that, have you found out?

Dr. Villanueva: We've been interested in understanding how different types of fat cells are programmed and we found an auxiliary factor that works with a central transcription factor that makes all fat cells. And this auxiliary factor programs cells to become white fat cells. And it turns out that this auxiliary factor, if you inhibit it, if you knock it out in mice, or if you delete it in mice I should say, this results in a switch from storing energy to burning energy and this results in the appearance of more beige adipocytes.

So the way we're thinking about this is if we can find ways to inhibit this molecule, it's called TLA3, we might be able to shift the balance towards energy expenditure and have more beige adipocytes.

Interviewer: So where are you taking this research now?

Dr. Villanueva: We're trying to understand the molecular action between this auxiliary factor TLA3 and another factor called PRDM16. PRDM16 is important in making brown fat cells and we have some evidence that TLA3 is able to inhibit the activity of PRDM16. These auxiliary factors are talking to one other in a sense. Understanding how this crosstalk is occurring, we may be able to identify ways of inhibiting that negative interaction between TLA3 AND PRDM16. And to do that we really need to understand how this molecular interaction occurs.

We've also identified a new player that may be able to disrupt this interaction in cells and this factor is called AES and it's induced with prolonged cold exposure in rodents during the time when these beige adipocytes appear. What we think might be happening is that AES is turned on to prevent interaction between these two auxiliary factors and allow the activation of the beige program.

Interviewer: So what have you seen in mice so far? What kind of manipulations have you done and which ones sort of makes the biggest impact?

Dr. Villanueva: One of the impacts that we've seen so far is that in mice that lack TLA3 and adipose tissue, we see pockets of these beige adipocytes. And so now what we're doing is studying the physiological consequence of that. We know that beige adipocytes consume glucose and lipids and so if they consume glucose, we might be able to see effects on glucose metabolism which has implications for diabetes. One of the findings that we've had is that these knockout mice have improvements in glucose when we challenge them with prolonged cold exposure.

Interviewer: The ultimate goal is to get I would imagine, the best conversion from white fat to beige fat.

Dr. Villanueva: As far as developing therapeutics, the way that we're thinking about it is that it's oftentimes easier to make a drug that will be able to inhibit a pathway rather than activate it. So since we know that TLA3 is able to inhibit this beige program, the idea would be to inhibit the actions of TLA3. We're starting to develop assays to be able to do that and to search for drugs to disrupt this interaction.

So I think there are going to be two ways to do this effectively and one way is to reprogram the cells and the other way is to stimulate these cells. They need to be activated and so typically they're activated with cold or they can be activated with drugs that activate the Beta 3 adrenergic receptor. One way to do this is if you could find sort of common [inaudible 00:07:18] therapies that would reprogram cells and then also activate these cells then you would have highly active beige fat cells that are metabolizing glucose and metabolizing lipids. The average American puts on about a pound of fat, which is around 3500 calories.

Interviewer: A pound of fat per...?

Dr. Villanueva: Per year.

Interviewer: Per year.

Dr. Villanueva: A pound of fat doesn't sound like a lot in a year. And if you break down those 3500 calories over days it's about 10 calories a day that you're consuming in excess of what you're burning. And so if you can have small effects on energy expenditure which would consume those calories you might be able to prevent the average weight gain that most Americans have.

Announcer: Interesting, informative, and all in the name of better heath. This is the Scope Health Sciences Radio.