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Week: 566.7 Guest: Dr. Craig Warden, Univ. of California at Davis, lead author UCP 2 study Topic: UCP 2 gene may regulate fat storage Producer/Host: Steve Girard

NEMA: At The Heart of the Matter, we try very hard to keep up with the latest news in the area of weight loss. Today we're with Dr. Craig Warden of the University of California at Davis, and lead author of a study which shows each of our cells may carry the switch that would allow our bodies to burn off fat...a gene that is responsible for making a protein called UCP 2 ... which seems vital in this process. Dr. Warden, how did you get onto this area of study?

WARDEN: I got interested in this area, really I've been studying genetics for obesity for almost 10 years, most of that while I was at UCLA. I came to the University of California just over a year ago and quite frankly I was looking for new projects which I could do which are related but different from what I did in L.A. to distinguish myself from my previous advisor. And so, this started out as a project where there are a number of known obesity genes. And I went out and asked 'okay, if we have known obesity genes, perhaps somewhere, there are already clones for other obesity genes'. And this is a holistic age and there are people who have as their small projects to clone every gene there is and make this information publicly available. And so, in fact, I went out and used the Internet to search public databases maintained by the NIH for obesity related genes, and was able to identify a gene that we call UCP 2... which was related to another gene called UCP 1. And this UCP 2 gene is a gene which we've gotten very excited about, and so even though the gene was sitting in a sequence database and somebody then somebody delayed sequencing. What we have done is to take that and the actual lab work and biochemistry required to show that this is a very interesting protein which burns calories and so may help us to lose weight by literally burning off fat.

NEMA: Seems there are new gene discoveries every day, and it's sometimes hard to keep them all straight...but I guarantee people who hear about this gene and its effect will remember it because it deals in weight control. Is UCP 2 found in all human cells?

WARDEN: Yes, all human cells would have the UCP 2 gene. Different human tissues though would make more or less of it. So the same way that people might be shorter or taller because of some differences in how much of one protein or another they make...we might also make more or less of this protein and in more or less of some tissues, so we particularly make a lot in our muscle and our fat.

NEMA: The things that I have read seem to indicate that if there was a way we could increase the production of this protein throughout the body, then we might be able to burn fat at a faster rate and make some progress on a very gradual and, and steady basis. Is that the basic explanation of how it works? Can you tell me more about how it regulates the temperature of the body?

WARDEN: Well yes, I mean, if you imagine your body needs some amount of energy just to maintain itself, some amount of energy to run and yet if what you do...if you increase the amount of, number of calories that are being burned and used for heat instead of being burned and used to run the body, then overall you have to burn more calories and so this would increase the total number of calories which are burned and so decrease the number that are stored.

NEMA: To many people, this news is going to be an eye opener...and get a lot of people leaping to capitalize on your discovery...a lot of companies that would stand to do well to get into the business of real fat burning. Have you seen that happening? I mean so much attention is paid to diet drugs, to help people to try to lose weight, and this seems like a more natural way of doing that.....

WARDEN: Well yes, this is a gene that if somebody had gone looking for it probably could have cloned 5 years ago or more. And so in part , it's my good luck that nobody did. But also what it means is that even when I and my collaborators each independently started to look at this gene and decided that really was interesting. We immediately got a concern that somebody else that we didn't know was looking at it and up until, maybe, yesterday or the day before that we didn't know that we were going to get beat. And so it's only very recently that we felt comfortable that in fact not only did we have the story, but we were going to be the first out with the story because in fact this protein could have been worked on by any, any number of people and, so I feel a little bit lucky that, well it was still available for us to look at.

NEMA: And I noticed in some of your literature about Duke's role and the French Research Scientifique in the whole thing too. Was that a true collaboration or was that a kind of working ahead and then check in with them thing. How did that work?

WARDEN: Oh, we've collaborated very intimately. We have a sort of daily e-mail club and each institution has investigators who have been studying obesity for many years and our joint expertise's are highly complimentary and have made the paper much stronger. So the group at the CNRS in France independently cloned the mouse UCP2 gene and then were able to show that that mouse UCP2 gene actually had the activity that we called the encoupling activity which makes the heat and this is absolutely a vital part of the paper. Whereas the group at Duke had an animal model of two different mouse strains that you put on a high fat diet, one strain stays lean, one strain stays fat. The strain that gets fat they were able to show that it produces less UCP2 then the strain that gets lean. And so these were all very important parts of the story and so we've been a highly complimentary and a collaborative research effort and we communicate with each other very frequently... it is unusual in part what we've calculated is each of us has only small or moderate sized labs and for us to remain competitive with large labs and large companies the way to do it is by taking advantage of the cynergy offered by essentially having a 24-hour lab that works from the west coast to the east coast to France.

NEMA: Sounds like it was a lot of fun to work on this. How long did it take for everyone to get up to speed on the other's work, and get the end?

WARDEN: Well, the actual UCP 2 work, proceeded fairly quickly, we started it last summer and so I think this has been really amazingly fast...in part because we've all used resources which have been produced for instance by the Human Gnome Project, so these Human Gnome Projects resources greatly aided our work.

NEMA: Now to get back to what it means to those who are having trouble attaining a healthy weight...and are looking at this news with a lot of hope. What does it mean to those people...and what can we expect next in this area...? A drug or something natural, that could be added to the diet that would trigger the effect?

WARDEN: Well, I mean, I think that they are still going to remain excellent reasons for people to continue to exercise and eat a healthy diet and that this doesn't change the need for people to do that and even to watch their calories. But there are people who already exercise, eat a healthy diet and who are overweight, and so who need some way, some other help and so I think this would be primarily for them. And our long-term goal then would be to make a drug or any kind of product, natural or otherwise, which would increase the activity of this protein and allow people to use their bodies to burn off calories.

NEMA: There are other applications for this find other than for people who are obese. Tell me what the other purposes might include for this UCP 2 gene and its protein...

WARDEN: We think this protein is involved in controlling the balance of energy use between body heat and body weight and so this is important to people who are overweight but there are other functions for people who are underweight, who are losing weight and who don't want to, this might also be important. So people who are just naturally or extremely low weight or people who have cancer or AIDS, it might be possible to promote weight gain by turning this protein off, by making it so the protein is less active and less calories are being burned for heat. This protein is also found in the immune system, there's quite a lot of it, and the white blood cells and so we think it might have a roll also in anytime where heat is generated so this would include fever and inflammation. And so some of the research questions we would like to ask is: what is the roll of UCP2 in fever and inflammation and could this be used in any way to provide any sort of therapy for those problems?

NEMA: I know this whole concept is some time from becoming applicable to obesity or inflammatory diseases....but what's next in the research area...what other questions do you have?

WARDEN: What we would do now is work with a drug company to find drugs which are safe and effective at increasing the UCP expression and this, I mean it's not an area of my real expertise, but I mean, I easily imagine this will take several years. We'll also have several research questions we'll ask, we'll look for different forms for the UCP2 and people and ask whether or not these forms can demonstrate they cause obesity. And in mice, what we would do is genetically modify the mice so that they increase or decrease the amount of UCP2 that they make and ask if this actually does cause changes in body weight. So we can ask basically that whether or not we can demonstrate in another way the roll of this protein in obesity.

NEMA: Just by thinking out the idea of some people running a couple of degrees cooler, some a couple of degrees warmer as a natural state... I was wondering, maybe there is a reason, another deep-seated reason we don't know, that their body wants to run that way....or do you think it's just a problem that should be fixed?

WARDEN: I don't know, I think that before we could observe that but we really couldn't think of doing anything about it. Perhaps now we can ask, I mean, what really is the healthiest way to be? Is it healthier to be overweight and low body temperature or to be, you know, lower weight and a slightly higher body temperature? And, as I think that this is a fairly fundamental question and it would be very interesting to ask.

NEMA: Is there something we may be eating or not eating that may increase or decrease the production of the protein?

WARDEN: Well, we know that fat can increase the amount of UCP2 in some mouse strains and so we would guess that if the same things happen in people, some people eating a high-fat diet might make more of this protein and that helps keep them leaner then other people eating the same high-fat diet who might make less and they would store more of that fat. So in fact we do know one thing that induces it and that's fat in the diet.

NEMA: Our thanks to Dr. Craig Warden of the University of California at Davis. Once again, new promise in understanding why some of use are fatter, and have more trouble attaining a healthy weight, or the weight we want...and a potential tool for helping those who can't keep weight on...including those fighting cancer or AIDS. The body's thermostat, or at least some of the wiring, may lie in the UCP 2 gene.

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NEMA: Thanks for joining us for today's program. If you have any comments or suggestions, contact this station. Or visit our home page at:

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...for a look at transcripts of this or past programs, or to find out more about the National Emergency Medicine Association. I'm Steve Girard at The Heart of the Matter.

NEMA: Isn't that funny, yea that's um, you know, there, there have been, you mean you try to follow the uh the diet scene and the books and the, and the programs and the things you see in all the different media um, it's amazing that people can make heads or tails out of, out of what to do in order to lose weight or, or you know get in shape. It's just amazing. They don't listen to themselves quite as often as they really should. Um, that was the last...(blah,blah)...well that's all I had. Is there some other aspect that you know, that, that really proved interesting to you,something that uh you know, that really kind of turned on the lights for you, personally maybe that uh that got you really excited about it?

WARDEN: Well what's really got me excited about this is just that this is a novel protein that may have a uh , a substantial impact on body energy balance and that this is uh , um and been a real pleasure for me to work on and something which I have been wildly excited about and um well I, I think it's been fun.

NEMA: That's Great...(blah, blah)....and sometimes getting on a personal side of things as to how you feel about the thing is, is kind of a little bit touchy, but sometimes I ask it.

WARDEN: I've been having a lot of fun. I mean this is uh, uh, um you know, uh I've uh, about 4 years ago I did a paper in uh, that was in science uh, maternal science and it got a fair amount of press , not as much as this one, uh, and that was sort of fun, but I think that this one is much more exciting and much more fun and so um, in a way I fell um, um, amazed that, that so many other people are sharing some of the excitement that I felt for so long.

NEMA: Great, that's wonderful.Um, okay , that's all I have. Um and what will happen is of course there'll be a beginning and an end...(blah,blah)

 

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