America's obesity epidemic has become, excuse the pun, standard fare on the menu of current national obsessions. And with good reason. Whether it's 20 percent, 40 percent or 66 percent of American adults who are obese — the figures vary by age group and ethnicity — it's clear that as a nation, we are not Olympics material. That's true of children as well; their obesity rates are also on the rise.
No wonder, then, that a relevant July 1, 2007, research report in Nature Medicine (entitled "Neuropeptide Y Acts Directly in the Periphery on Fat Tissue and Mediates Stress-Induced Obesity and Metabolic Syndrome") was headlined and blogged around the globe.
The study, conducted in mice at Georgetown University Medical Center's Department of Physiology and Biophysics, proclaimed that researchers have found the biological switch that promotes obesity. And it was chronic stress of a particular kind — the kind that we might confront on the job, for instance — that literally turned that fat switch on.
UCSF's stress and physiology expert, Mary Dallman, PhD, has been studying the effects of chronic stress on the brain and body for more than 30 years. She has a particular interest in glucocorticoid receptors, which are found in every cell type in the body. Why they are so fascinating, why this latest research demonstrates that our biology is a mismatch for our high-stress lifestyles and why pleasure is at the root of everything are just some of the subjects we cover in this edition of Science Café
- Neuropeptide Y Acts Directly in the Periphery on Fat Tissue and Mediates Stress-Induced Obesity and Metabolic Syndrome
- Nature, July 1, 2007
- Mary Dallman, PhD
- Gut Feeling About Stress
- UCSF Daybreak, April 15, 1997
- Tackling Obesity, Part 4: Exploring the Intersection Between Mind and Body
- UCSF School of Medicine, July 6, 2004
Jeff Miller: I'm here today with Mary Dallman, an expert in the neural arrangements that define the effects of chronic stress on brain and body which is kind of a mouthful for saying that stress has both good and bad effects. Mary, could you tell me something about your research — I know you've been at it for a long time — and could you give me a summary of what you've been doing? And what your findings have been over the years?
Mary Dallman: Well, you have to know first that I fell in love with the glucocorticoids, which are the adrenal stress hormones, when I was in college. And I've never, never stopped loving them and trying to find out what they do. So much of what we do in the lab is trying to answer the question both for brain and body what the role of the glucocorticoids is with stress and particularly chronic stress.
Miller: Now these are in every cell type in the body, correct?
Dallman: The glucocorticoid receptors are in every cell type in the body if not every cell.
Miller: So what have you learned about... You've said that you've been in love with them since college days, so clearly there was some particular fascination about this as opposed to other avenues you could have pursued?
Dallman: I was a chemist and I loved their structure, and then I became a physiologist and I adored the fact that they are protean hormones that do almost anything you want them to do. They can make you fat, they can make you thin, all depending on the context in which the body is when they act. They can make you learn; they can make you forget. They can make you eat a lot. They can make you fight.
Miller: So let's go back to the fat and thin part since obesity is sort of the topic of the day. How does that work?
Dallman: When the glucocorticoids are secreted and the animal... I have to back up. When animals are exposed to increasing amounts of glucocorticoids without any stress they become fat. They lose muscle and they gain fat, and more than that, the fat is in the belly. That is a very clear action of the glucocorticoids that requires increased insulin secretions as well. Which they do. However, when the animals are stressed and only have chow to eat, and glucocorticoids are varied in the same way, the animals may get thin rather than fat because stress induces the action of the sympathetic nervous system. And the sympathetic norepinephrine secretion melts fat in the presence of glucocorticoids.
Miller: So let's talk for a second about what exactly stress is. I think a lot of people have some notion about how it feels to be under stress, but what exactly is happening inside their bodies?
Dallman: Well, if you're stressed and if you're challenged by something and can't get away from it and can't relieve it behaviorally or in some other fashion, and if this persists, then the brain changes and the stress input activates a limbic emotional brain to recruit pathways in the brain that alter behaviors, alter neuroendocrine function, alter autonomic function, and basically alter the way the brain responds to various new stimuli. In the body the elevated glucocorticoids secreted with stress decrease protein synthesis and increase fat synthesis, and increase glucose synthesis — all very sensible if you need to get away from stress. But not so good if you can't get away from it.
Miller: So because of the energy stored in the fat because you might need to flee?
Miller: Because you might not be around regular food supplies or whatever?
Dallman: Exactly. If you don't have stores for energy, you can't move very far and die on your way.
Miller: So it's a beneficial evolutionary response?
Dallman: It's marvelous evolutionarily, because there hasn't been the enormous availability of corner food stores and McDonald's and endless inexpensive food that there is in our society.
Miller: So is that related to why these food centers in our brain tend to light up around sweets?
Dallman: Ah. The glucocorticoids also make you enjoy things more, such as sweet foods, such as drugs, such as fat foods. And I think there is work now showing they generally act on the brain to make you want more of whatever is ongoing in the environment. So if you've got a bucket of ice cream you'll eat more of it if your glucocorticoids are high; if you are going to be angry at somebody you will be more angry if the glucocorticoids are high.
Miller: Is it then, since stress is evolutionarily beneficial, that it is the inability to escape the stressor in modern life that seems to be one of the triggers?
Dallman: I think so, yes. Yes, definitely. You can't run away from a bad boss unless you change jobs, and that has its own uncertainties.
Miller: The recent study that was reported in late June, early July 2007, regarding the biology of fat, into which you contributed a commentary for the journal Nature Medicine, it suggests that maybe our biology is a mismatch for our current environment, this highly stressed stuff-your-face kind of world in which we live, at least for many modern Americans. Is that a fair assessment of that study?
Dallman: Yes, I think so. I think it's a terrific study. What it did for me was complete a loop that I didn't understand in our rat studies and that is that in the presence of high-carbohydrate, high-fat diet plus stress there is increased secretion of neuropeptide Y through the autonomic nervous system into fat depots, and that increased neuropeptide Y secretion inhibits the actions of the catecholemines that are secreted also from the autonomics, and increases fat cell proliferation and vascularization.
Miller: So let's break that down a little bit. So neuropeptide Y actually controls the pathway that determines how many fat cells are made and how much fat is deposited?
Dallman: Yep. Yep. And it's been known for a long time that neuropeptide Y and norepinephrine exist in the same neurons in the sympathetic nervous system. And it's also been known with low stimulation that norepinephrine is secreted, but with high levels of stimulation of these sympathetic nerves you get secretion of both norepinephrine and neuropeptide Y. This study by Zukowska and her co-workers showed that with high levels of intense stresses they got NPY secretion into the fat depots, whereas with low levels of stress they did not.
Miller: So this is mice...
Dallman: This is mice.
Miller: Ok. Again, just so that we're clear... Mice under stress — I'd like you to describe the kind of stress that they put the mice under — were fed a high-sugary diet.
Dallman: High-sugary and high-fat.
Miller: High-fat. And then there were mice fed a similar diet who were not similarly stressed.
Dallman: That's correct. And then there were two more groups of mice who were fed only chow. And only the mice who had high-fat diet increased their fat depots but strikingly the mice that had high-fat, high-sugar diet and stress — intense stress — got fatter than the animals that only had the pleasurable diet.
Miller: So describe the kind of stress that the mice were put under, so that people really can understand how this heat might equate to their workplace environment.
Dallman: (laughs) Well, the mice who did respond in this way to stress were stressed with standing in cold water — ice cold water — for an hour a day for 14 days, or they were stressed by being, ha, social subordinates and were threatened heavily by social dominant mice. Now that you could directly relate to the workplace.
Miller: (laughs) How much time were they exposed to this stress?
Dallman: For an hour a day.
Miller: Not eight hours...
Dallman: Not eight hours. Just one. However, I suspect most people who are heavily stressed by the workplace are not exposed to their bosses for eight hours a day too.
Miller: So this is in mice...
Dallman: This is in mice. But I also want to say that two other stresses did not produce the same effect.
Miller: These were?
Dallman: These were much lower intensity. They were either being put in a tube where they couldn't get out for an hour a day, or they were standing on a platform above water — but not in cold water — for an hour a day.
Miller: So what does that subtle difference say about the triggering mechanism?
Dallman: I think it says you really have to push the sympathetic neurons to fat to cause NPY secretion plus norepinephrine secretion rather than just norepinephrine.
Miller: So again mice, as they relate to humans... many findings in mice do not always translate exactly or even closely to humans. So what type of things might be fundamentally different and not work in humans should this ever get to a clinical trial phase in humans?
Dallman: Well, first they have to solve the problem. I think we haven't said that the group found that the neuropeptide Y was acting through specifically Y2 receptors in the fat depots, both on fat cells and the blood vessels, to cause proliferation. These receptors do exist in people and in people's fat cells and in their blood vessels but there's a whole host of neuropeptide Y receptors in people and in mice and the ratio of the receptors may be different in people than they are in mice. That's one possibility. So that you might not have the same effects of infusing Y2 receptor sector antagonists which is what the Zukowska group showed was so effective in blocking the fat formation in stressed animals.
Miller:Anything else that comes to mind?
Dallman: Delivery of the drug, I think, is going to be a really tricky proposition.
Miller: I’m glad you brought that up, because what I've read about it says that they’re interested in licensing the technology. So is there anything that you know about the specifics of this? Is it licensable?
Dallman: No, but I don't know what represents licensable. I mean patents or licensing is something that I am completely unfamiliar with.
Miller: There was some talk too about reconstructive and cosmetic possibilities for this technology. What do you think about that?
Dallman: Well, what I gather is that rather than infuse an antagonist to the Y2 receptor, they plan to infuse NPY, and they have shown that if they do infuse NPY they can increase — in mice — the fat depot.
Miller: I have to ask, too: You know this American penchant for the magic bullet, and clearly these results could be achieved by diet and exercise, the old standbys. Is even the prospect of something like this a bad thing, do you suppose, psychologically for the American people as we confront this obesity epidemic?
Dallman: Yeah, I think it's a lousy idea, actually, because it doesn't change the head at all. It may change — if it works — the prospect for ultimate metabolic health but really what you need to do with a chronic inescapable stressor is to figure a way of dealing with it. And even if it's inescapable you can put your head in another place and perhaps meditate or perhaps read a book and get away from it enough so that you gain more perspective.
Miller: And I guess if you think about the negative effects actually accumulating to the point where it drove you to do something about it, if there were no such negative effects than perhaps you would persist in a situation that was otherwise not healthy for you.
Dallman: Absolutely. Absolutely. It takes energy to get away from it, but it's worth the energy to revise your head to the extent that you can deal with the stressor.
Miller: I want to circle back one second to this idea about mice and humans because I'm wondering would there ever be, do you suppose, if this type of approach did work in humans, genetic profiles that would make it more likely to help one group over another? I mean, is that a possibility?
Dallman: Sure. Absolutely it’s a possibility.
Miller: Again, because of the variation in neuropeptide receptors…?
Dallman: In the receptors, and actually one of the interesting things about the Y2 receptors, which are the ones that are important for accumulation of fat, is that there has been a genetics study in mice showing that Y2 receptors associate very, very strongly with mesenteric or intra-abdominal fat which is the kind of fat that has been shown to be worst for us in terms of outcome.
Miller: This is all part of that metabolic syndrome?
Dallman: Yes, it is part of the metabolic syndrome.
Miller: With the associated high cholesterol, high blood pressure, early diabetes, all of those things.
Dallman: And also the paper in Nature Medicine by Zukowska showed that they had metabolic syndrome-like effects, with the chronic stress and the high-calorie diet.
Miller: So would you view this paper as a milestone in this area of research?
Dallman: I think it's very important just because they've connected what happens in the head with what happens in the fat in people who can eat ad lib, or potentially connected that.
Miller: I know you've had a very long career…
Miller: So was that connection at all obvious or respected as a possibility when you began, I won't say how many years ago?
Dallman: 37. Actually, longer than that. No, it was not expected and…
Miller: Or respected?
Dallman: Respected? Lord, no. No, that's one of the wonderful things that's happening and I think probably through human scanning, MRI and pet studies, where it's becoming quite clear that the head runs the body and what happens in the head very, very much determines how the body responds to various things.
Miller: A once very radical notion…
Dallman: A once highly radical notion.
Miller: Well, let's talk about your latest work and what avenues you might be pursuing these days.
Dallman: Well, one of the things we've been focusing on for the last year or so has been pursuing a finding that came up a couple of years ago in the lab, which showed that increased glucocortociods caused increased lard eating absolutely in proportion. Rats were given chow to eat and a bucket of lard separately. And it turns out...
Miller: I’m grimacing here.
Dallman: (laughs) You are grimacing. It turns out that rats will just snarf down the lard. Rat chow is exceedingly boring and is pretty low fat. And rats like fat. So with a separate bucket of lard the rats will nibble at the lard and they’ll compose diets that are about 50/50. And as you increase glucocorticoids, they’ll go up higher and higher in their lard ingestion — they’ll go up to 70%. But we did a study in which we made the rats diabetics so they had no insulin. And all of a sudden the glucocorticoids had no effect on lard eating at all. And unlike that, they finally had an effect on the amount of chow that was eaten. So in the absence of insulin the glucocorticoids increased chow eating; in the presence of insulin the glucocorticoids increased lard eating. That was absolutely clear, but we were wondering why and how. Or where. And so in the first studies for other reasons the vagus nerve from the liver to the brain was cut. And that also induced lard eating in the animals that had no insulin. And we felt that we really had to pursue this and find out where the insulin was acting or how to cause lard eating in animals that otherwise had no insulin.
Miller: And what have you found?
Dallman: And what we've done is cut all kinds of vagus as well as stopped the afferent traffic from the liver to the brain, and it turns that it's the signal from liver to brain that normally, when there's no insulin around, inhibits the intake of fat. And that's as far as we've gotten on that except that we have clear evidence that when lard is eaten by rats the brain pleasure centers turn on, and that probably explains why the glucocorticoids are so important in this because they seem to turn on the pleasure center and through that mechanism cause many different behaviors.
Miller: In the end it always comes back to pleasure, doesn’t it?
Dallman: It does. Reward is good.
Miller: Before I let you go, I must ask you one last question and that is you have been alternately referred to as a neuroscientist and a physiologist and I'm just wondering, how do you see yourself, so that we can properly label you?
Dallman: (laughs) I don't like labels. I’d rather be unlabeled, but I identify myself as a physiologist, and the reason for that is that I think neuroscience is a subset of physiology and is incorporated into the study of how things function as a prime mover but not the only one.
Miller: Well the next time I interview a neuroscientist I will ask if they actually agree with that definition.
Miller: Mary, thank you so much for joining us on Science Café today.
Dallman: Thank you.