Andrew Whittle, Institute of Metabolic Science, Cambridge
This week, scientists at Cambridge University have identified a signal that controls the activity of brown fat – that's a special kind of adipose tissue that's used to generate heat in the body by burning calories, and it’s thought that boosting the activity of this brown fat could help people to lose weight. So people think it could be a very important therapeutic target.
Dr. Andrew Whittle is from the Metabolic Research Laboratory at Cambridge University and he’s with us to tell us about this piece of work, published this week in the journal Cell.
Chris - So fats aren’t all made equal then? We’re not just one blob of adipose? There are different types of fat that do different jobs.
Andrew - There's definitely not just one type of fat, no. And we’ve known for a long time that in small children, small babies, and also small animals like mice, you have this other type of fat which isn't the white fat that stores all the fat. But instead, it looks brown in appearance because it has lots of these mitochondria, the powerhouses of the cell. And it was thought for a long time this wasn’t present in adult humans. But research over recent years – thanks to new imaging techniques – allowed us to find and locate active depots of this brown fat in adult humans as well.
Chris - And where do you find it?
Andrew - Very much in a similar location to where you find it in small animals. So, around the shoulder blade areas, behind the collar bone, in the bottom of the neck.
Chris - And its role is chiefly to burn energy in order to make you feel hot?
Andrew - Yeah, I would say the prime reason that brown adipose tissue exists is that it’s evolved to help maintain cold body temperature. So, as mammals, we depend on maintaining that temperature to function properly and this tissue helps animals to do that.
Chris - And if it burns calories of course, it’s another way of getting rid of excess energy and one of the things that we’re very good at, although looking at the population these days, you could be fooled into thinking we’re not. Actually, we’re very good at regulating body mass, aren’t we because despite in some cases, eating huge amounts of excessive food and then the next day eating too little, we keep our weight – despite these dramatic changes – really quite stable. Is it because it gets dumped into this brown fat and the excess calories do get burned off and you just turn them into waste heat?
Andrew - It’s possible, but I think we don't have the evidence to suggest exactly how brown fat is regulated in that kind of way in humans in terms of its acute regulation but it’s a potential that some of those calories are being burned in brown fat. Certainly, in animals like in mouse models, we know that you can stimulate the brown fat more if you feed a high calorie diet, so it does respond to that.
Chris - And you’ve found a signal that enables you to manipulate the activity of that fat – how metabolically active it is, how many calories it is burning off.
Andrew - Yes, so basically, the protein we identified and it seems to prime the brown fat to be able to respond better to the traditional nervous activation of the tissue. So, when you take this protein away, the brown fat is less able to burn calories to activate itself to make heat.
Chris - So under normal circumstances, the signal comes from the brain via nerve cells into the brown fat and tells it, “Right now, you have to ramp up your metabolic rate” and there's an additional cue which is the one you found?
Andrew - We think this protein is sort of a mechanism to enhance the impact of heat production. So, when you have prolonged exposure to a cold environment or that the body senses, or the brain senses, that you're eating a much higher calorie diet, in order to get even more heat out of the brown adipose tissue, it starts to make this protein, this bone morphogenetic protein 8b which is the one we found or BMP 8b. And that enables the tissue to respond to a greater extent to the same level of nervous stimulation.
Chris - Where does that signal come from? Does it come from the brain and go in the bloodstream or does it come out of nerve cells or a combination of the two?
Andrew - The BMP 8b signal is made by the brown fat itself. In fact, one of the very interesting things we found in the paper is that BMP 8b is very specific in terms of where it’s made. So, it’s only really made in the brown fat and we found some in the brain as well. It was present in the brain. We went in to look at that and also, the only other place we really detected meaningful amounts was in the testis.
Chris - Wow! So does that explain then why women tend to gain more weight that men? If you look in the population, you do find that a higher fraction of women who tend to put on a bit more weight – because I mean, it benefits them to do so from a child rearing point of view, doesn’t it?
Andrew - Yeah, I mean, whether that's because they don't have as much BMP 8b because they don't have it being produced in the testis, whether that's the reason, I doubt it very much. I think there's many more differences about women that may drive that difference in the weight gain phenotype if you like.
Chris - But the BMP 8b, would that come out of the testis or the brain, or other tissues and make its way in the blood to the brown fat? Will it see that signal and respond to it or is that just going to wash around and do other things in the body?
Andrew - The previous evidence from BMPs is that they act mainly in a more autocrine or paracrine manner, so they're not secreted like hormones generally. And we think that in BMP 8b’s case, that's probably the case at the moment. We don't have any evidence to suggest otherwise and it’s enough that's it is made in such large amounts in the adipose tissue that it functions there. But also, we found that it’s present in the brain and as well as this ability of the BMP 8b to improve how much heat the brown fat makes in the periphery, we found that actually, when you put BMP 8b into the brain, you get a very specific central effect. The actual BMP 8b in the brain stimulates more nervous activation as well. So it hits on both levels.
Chris - Effectively it’s turning up the thermostat in your body, isn't it?
Andrew - Yeah.
Chris - So, what is the BMP 8b actually doing in the adipose tissue? Is it just triggering other cells in saying, “Right, turn up your metabolic rate “ and if that's the case, how does it actually get made? What's the signal that tells the fat to make it?
Andrew - Well, we think the signalling in brown fat to make BMP 8b is just the fact that you get this nervous activation of the tissue saying, “Come on. We need to make heat. We need to stay warm” and in order to do that more efficiently, the tissue sets itself up to make as much heat as possible. So the BMP 8b in the tissue sensitises it to the adrenergic stimulation, it sets up all the enzymes that need to be there ready to burn the fat, and basically, just ramps everything up a notch so you get more heat production.
Chris - And can we simulate that effect? Are there drugs that can mimic that effect because if you could pop a pill and just make your brown fat more active, you could burn off excess calories if you're trying to lose weight or you had a heavy night last night and you think, “I feel a bit guilty now. I’d like to shed the excess caloric burden”?
Andrew - There are certainly drugs that already exist that hit the sympathetic nervous system or I mean, thyroid hormone for instance or if you did thyroid replacement therapy, there's evidence that that drives more brown fat formation. But the problem is that these current drugs, they're not very specific for activating the brown fat and so you get lots of other side effect which means you can't really use them as an effective drug or safe drug. One thing about BMP 8b that we think it makes it more interesting is, if we could develop a new way to target that pathway, that BMP 8b’s signals through, it does seem to be very specific to this thermogenic mechanism. We didn’t really find any evidence in our studies to suggest that BMP 8b does other things to metabolism and changes other aspects of physiology.
Chris - Does it keep the cells alive? Is it trophic? Is it a growth factor for brown fat because one argument I've had is that over your lifetime, you lose your brown fat and this is why people tend to gain weight or have a tendency to put on more weight and feel the cold as they get older, because they lose this tissue? Does it help to sustain the tissue if you have more of this BMP 8b signal?
Andrew - No, I think it’s important to make that distinction. It’s slightly different to some of the other strategies that groups are working on to enhance brown adipose tissue function. We have found that the BMP 8b in brown fat just regulates the mature cells which are already there and makes them more active. However, its role in the brain, with its ability to increase the nervous tone, that could be trophic. So, if you have more tone to the tissue, that's known to be a survival factor and a recruitment factor for more BAT (brown adipose tissue) so potentially through that mechanism, yeah.
Chris - That's Dr. Andrew Whittle. He is from the University of Cambridge Metabolic Research Laboratory and he published the work he’s just been telling you about this week in the journal Cell.