Hosts: Mignon Fogarty and Adam Lowe
Transcript: This episode originally aired December 27, 2005
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THE THRIFTY GENE HYPOTEHSIS
Mignon: There's been a lot of news the last couple of weeks about obesity.
Adam: It certainly is an epidemic in the U.S. At least.
Mignon: They've found when they do research on mice, when mice are kept on dry kibble, they pretty much regulate their weight pretty well. But when they're put on a cafeteria diet, which is what we're exposed to – unlimited choice – mice balloon up just like we do.
Adam: One of the thoughts in terms of obesity is when people lived in a time when food was not abundant, there was a benefit to being able to store a lot of fat. So when you hit the lean times you are able to survive. So there is a lot of talk about diabetes and obesity and the “thrifty gene” hypothesis. Again, the idea being that people might have had a genetic background that in the past would have been very advantageous to be able to store a lot of fat and survive through winters where there wasn't a lot of food availability, or various kinds of famine, but in today's world, the developed world where food is abundant, it can be problematic when you start building up a lot of fat.
OBESITY IMPAIRS MEDICAL CARE
Mignon: One thing that has really come out in the last few weeks is that not only is obesity a problem for long term health, but it's also becoming a problem just for doctors trying to deliver medical treatment to patients. There are now so many overweight people that doctors are starting to have problems delivering just regular medical care.
For example, there was a story that was pretty widely circulated, where (a small study , only 50 people), found that only 25% of patients in the study who got an injection into their buttocks actually receive an intramuscular does of the drug they administered.
In this case it was only a placebo, but a lot of important drugs are delivered by this route.
And perhaps even more alarming, the needle didn't reach the muscle in any of the women in the study. Not one. Not one woman got a dose of the drug, presumably because women, you know, we have a little more padding down there.
Adam: And for people to understand, the reason why they do those intramuscular injections is that muscles have a really incredible blood supply. So it's a very good way to get drugs into the blood supply very quickly. Fat tissue doesn't have a very good blood supply, so it really goes against what you are trying to do with an intramuscular injection if it goes into the fat tissue. Instead it doesn't get where it needs to go.
Mignon: And it can even cause an infection in some cases if it gets into the fat tissue because it lingers there.
Adam: It's pretty amazing to think that so many people aren't getting injections into their muscles. And it probably wasn't that long ago that physicians began doing intramuscular injections, and I think it is an indication of how much obesity has grown in the population in not that long a period of time.
Mignon: One thing I heard as a recommendation in the stories was that doctors might consider using longer needles, or perhaps giving injections somewhere other than the buttocks where it is easier to reach the muscle.
Adam: What happens if you are a skinny person and you get one of those long needles.
Mignon: Ow!! It's goes all the way to your bone?! Doctors are going to have to be more careful about individualizing treatment, not in terms of personalized medicine, but just in terms of what size needle they choose.
NEXT: Obesity is a problem for radiologists too.
Mignon: Then I did some investigation and I found that injections aren't the only problem. In fact, radiologist have been struggling with how to deliver good care to obese patients for quite a while. It's been a hot topic at the annual meeting of radiologists for at least the last couple of years.
There was a doctor this year, Dr. Raul Uppot, who is an assistant radiologist at Massachusetts General Hospital and a radiology instructor at Harvard University Medical School, and for the last couple of years at this annual meeting he's been talking about how the scanners, so MRI machines and CT scanners and some kind of ultrasound machines aren't big enough for obese people who are coming in for medical care. And he says he''s talked to technologists who do the scans, and that they run up against this problem every single day. And it's frustrating for patients too because they can't fit into the machines, they can't get the scans they need.
And he's talked to venture capitalists who see that the market of obese people is undeserved and therefore a market opportunity.
Adam: And probably also because these are obese people they probably have more health problems.
Mignon: That's right they may need these scans more than most people.
Adam: It's really frightening that again the percentage of people who are obese is growing and just the extent of obesity within those individuals seems to be going up and up.
Mignon: Right. In fact, obesity surgery is the fastest growing area of elective surgery in the abdomen.
Adam: And it is pretty incredible because I think there are quite a number of risks associated with surgery that people go to such extent to try to deal with their obesity problem.
Mignon: There are. Dr. Uppot also pointed out that not only is it these scanning devices, but hospitals are also having to purchase larger wheelchairs and bigger beds. It's effecting a lot of different areas of health care. For example, he said that a typical CT table can't hold someone who weights more than 425 pounds and a typical MR unit can't hold someone who weights more than 325 pounds. You know, these people who are quite obese I think are still a minority of the obese population, but that is a growing population.
Adam: In more ways than one.
Mignon: Yeah, in more ways than one.
A BETTER WAY TO MEASURE OBESITY
Adam: So what are the different metrics and standards used to evaluate obesity these days?
Mignon: Well, in the past Body Mass Index (BMI) has been the most popular method, and it has also been, when they look at obesity as a contributor to things like cardiovascular risk factors, they also often use body mass index as a measure. But there have also been studies out in the last couple of weeks showing that waist-to-hip ratio is a much better indicator of cardiovascular risk than body mass index, so they are suggesting that they switch to this new metric. Which is great, because it is also a an easier metric to measure – waist-to-hip ratio – because body mass index is a pretty complicated calculation.
Adam: And something people could even do at home.
Mignon: Right.
Adam: So how is waist-to-hip ratio measured?
Mignon: Well it's very simple. You get a tape measure and measure your waist and measure your hips. You divide that waist number by the hip number.
It's a little different for men and women. If you are a woman the waist divided by the hip should total under 0.85, and if you're a man it should be under 0.90 to be considered healthy. So if you get over those numbers you are considered to be in a higher cardiovascular risk group.
Adam: I think one thing that I heard about some of the BMI (body mass index) measurements is that is someone is really athletic or muscular they could actually have a very similar result to someone who is obese, but that's not the case for waist-to-hip ratio.
Mignon: That's right. If you're super muscular and extra fit your waist is still going to be smaller than your hips.
WHY BELLY FAT IS BAD
Mignon: One thing that is really fascinating is that the waist-to-hip ratio is also a very good indicator of the amount of abdominal fat. And what researchers have found just within the last 5 or 10 years is that fat in your abdomen – that abdominal, visceral fat – is different from the rest of the fat in your body. It's actually very metabolically active, which means it is secreting molecules into your system. And they have found that it secretes cytokines, which are inflammatory molecules, that have been implicated in all sorts of diseases including cardiovascular disease. And it wasn't that long ago that researchers thought of fat as a very inert substance. So then to find that fat in different parts of your body have different metabolic activities is very interesting.
Adam: I believe there is a really good correlation between that mid-visceral fat and insulin resistance and type II diabetes. Also a huge extent of mid-visceral fat – that fat that sits in between organs – can, I believe, present a lot of other medical problems as well. Things like surgery can be very difficult in very obese people.
Mignon: That's right. In your abdomen there is still subcutaneous fat that sits under your skin and then there is also that visceral fat that is actually surrounding your organs and secreting those cytokines and that is just very bad.
Adam: Mignon, I remember many years ago when I was doing laboratory research, and doing some surgical procedures on rats. And if you ever saw the inside of an obese rat, it's just very hard to find the organs because they become so buried in all the layers and layers of fat. It looks like an anatomy chart when you are working on lean rats, but when you work on obese rats its just incredible. The best way to describe it is when you get a large box full of packing material and there is a small little present buried deep inside and you have to dig around to find it.
Mignon: Wow, that is probably pretty motivating when you see that.
Adam: Yeah. The organs get buried in all this fat. So you see that and you think, “I think I'll try to keep myself lean if I can.”
Mignon: Well, what's also really interesting is that it's not hopeless.
I had an interesting experience last year. I was working out with a trainer and she told me to do lots of sit ups and I would lose weight around my waist. And I said that's ridiculous, I know you can't spot reduce. And she said, I don't know why but I see it in all my clients.
And she was right, I worked out really hard and I lost about 3 inches around my waist and only about a half inch from my hips. And I just know you can't spot reduce so I went and did research to find out what could be causing this, and I found that just within the last 5 years or so, that when you lose weight through exercise, you preferentially lose that visceral fat around your abdomen. And I don't know if they know why yet, but they are some very interesting studies where they found people who lose weight just through exercise and then just through diet, and then just through diet and exercise. And only the people who lost weight through exercise lost significant amounts of that visceral fat internal that surrounds your organs.
Adam: So more good encouragement to keep yourself active then.
Mignon: Yeah. So that old adage that a calorie is a calorie isn't true. There's more to health than just the sheer energy balance. Exercise has benefits above and beyond what you can do just through diet.
Adam: Certainly. I think there are a number of known benefits from exercise. Some of them aren't proven yet but are theoretical. So exercise with weights helps keep your bone strength, helps keep your muscle mass, which can deteriorate as you get older; aerobic exercise improves your cardiovascular fitness, and then there may be some other benefits because as you do more exercise you may start to increase the number of certain kinds of receptors as you build muscle that help with insulin signaling and there may be some benefits beyond the obvious ones in actually helping to prevent diabetes and obesity because of metabolic changes that happen when you exercise.
Mignon: Boy! I'm going to go exercise when we're done here. I'm itching to get out for a walk.
Adam: But it is also important to remember that exercise absolutely helps, but also you should still remember the caloric balance and remember whatever you take in and don't expend is going to go somewhere.
Mignon: That's right. It doesn't do any good if you burn off 200 calories and eat 400.
Adam: That's right. It's not a license to eat 20 candy bars if you go for a walk.
ARENA'S SEROTONIN RECEPTOR DRUG LOOKS PROMISING
Mignon: Well, there's also some interesting news on drug trials. For some people it's very hard to regulate their food intake, and so pharmaceutical companies of course are hard at work on that. It's a growing market. A company called Arena pharmaceuticals just had positive results from a phase IIb trial on a diet drug called APD356, a very exciting name right now, I'm sure when it gets farther along they will give it a snazzy name. But what it does is activate receptors called 5HT2C receptors, and it enhances a feeling of satiety. So they are hoping that – and they've seen positive results – so it seems like this drug helps people feel full.
Adam: I think that is different than other drugs that were used in the past. Because often stimulant drugs were used to help with dieting that had a lot of negative and potentially dangerous side effects. So there's hope that this pathway working in a way to help people feel full will have a lot of the benefits without the negative side effects.
Mignon: That's right. And this specific receptor is actually a serotonin receptor. And it's the same receptor that was the target of the drug combination “phen-fen”, the Phentermine and fenfluramine ...which actually resulted in cardiovascular lesions. You know, people have those heart valve problems from phen-fen. But, Arena believes that so far their drug hasn't show any of those problems, and targets the receptor with a little bit more specificity than those older drugs did.
Adam: I was thinking back to the old days when people would try to take stimulant drugs to reduce appetite and burn off calories.
Mignon: That's been determined to be pretty much unhealthy.
Adam:Yeah, that's quite dangerous.
Mignon: Well, so far Arena says their drug has been generally well tolerated and it's just a phase II trial, so it is a small trial and it will probably be years before they complete a phase III trial and this drug would become available; but it's an interesting step building on previous drugs that were known to work but had dangerous side effects. So hopefully they can tweak that drug a little bit and make it safe and retain it's efficacy and then provide help to people who have trouble dieting.
CALORIE RESTRICTION, SIR2, RED WINE, AND LONGEVITY
Adam: Going from obesity to the other end of the spectrum, a lot of people are doing research and looking at caloric restriction as a way to increase longevity and health. And scientists are getting more of an understanding of how this is working, and it seems as though there are some pathways that are activated during states of starvation that make a big difference in the apoptotic process – programmed cell death. And another thing they are looking for are, number one, what are the effects of caloric restriction -- how do you make it safe and healthy in some way, but also are there ways to turn on the beneficial pathways without the caloric restriction. And one thing they found is that there may be compounds in red wine that actually turn on the same pathways that get turned on during caloric restriction, and there's some thought that this may be the answer to the French paradox, which is why is it that people in France often have a very high fat diet that we think can be dangerous, but are very lean and don't have this big risk of cardiovascular disease that you would expect from that kind of diet.
Mignon: Well. I'll have to drink a toast to those researchers tonight.
Adam: Absolutely! One of the things they did find was that grapes grown in harsher climates or colder conditions seem to have a greater concentration of these resveratrols, these compounds that seem to turn on this pathway where one of the genes is called Sir2, so wines like Pinot Noir have a higher concentration than Cabernet Sauvignon .
Mignon: That's fascinating! So is Sir2 one of those genes involved in apoptosis?
Adam: So, one of the things that it is though of the Sir2 gene is that it can induce certain DNA repair factors and those factors can help inhibit pro-apoptotic factors-- in other words, factors that cause programmed cell death – to try to sequester those pro-apoptotic factors away from mitochondria, and by doing that inhibit stress-induced cell death. So it's possible that increasing the expression of the Sir2 gene may help promote long term survival by helping important cells that might be hard to replace to survive in the body during times of stress or just in general survive longer. So this seems to be activated in conditions of starvation or caloric restrictions. But again it also looks like there is a chance they can be induced by compounds like resveratrol in certain kinds of red wine.
Mignon: I know there have been some studies completed in dogs showing that their lifespan was increased by calorie restriction and there are primate studies going on where...you know primates live longer...I don't think they have the final results yet... but they have found that the older primates that have been on calorie restriction are much healthier than the ones who've been fed a normal diet. They have less diabetes and heart disease and things like that. So, you know, these are mammals. They aren't worms or flies. So, I think everyone believes this will be applicable to humans, although no studies have been done to show that, and we certainly can't say until the studies are done. But not only could calorie restriction help people live longer, but also be healthier in old age. Which is something when you think about life extension, a lot of people believe that they wouldn't want to live longer because old age is filled with the hardship of illness, but one promise of calorie restriction is that not only would you live longer, but your final years would be healthier.
Adam: And one thing that is amazing is that it looks like these pathways function in similar ways through many different organisms, not just animals, but going back to yeast. So yeast and then fruit flies, and now there are these mammalian studies going on, seems to indicate that this is a pathway that is maybe conserved across many different forms of life.
But, one thing people should know though if anybody wants to try to replicate this (and it's not proven yet) a critical thing for people on caloric restriction diets is to make sure they are getting adequate nutrition. It's not a very easy thing to do, number one, because it's probably something in the range of a 30% to 50% reduction in the calories one would intake compared to recommended caloric intake; but it is also very hard to get all the nutritional needs, so you need to make sure you're getting the right nutritional supplements because you can get deficiency diseases if you're not getting adequate nutrition.
Mignon: Right. I have heard that as well, that it's very complicated, as we all should anyway, people (on this diet) focus their diet on nutrition dense food. Things like kale that already have huge amounts of vitamins in them relative to the calories that they provide. So, you can do it, but it requires an enormous amount of planning.
Adam: And also anyone who is considering doing this kind of thing should definitely consult with their physician, to put together a plan that would be healthy for them.
Mignon: That's right. I have tried it for a few weeks or months at a time before, and it is very hard.
Adam: I've tried it too. I don't know that I've measured calories, but I take vitamins so I try to get things that way. But I can, for stretches of time, dramatically reduce my caloric intake, and got really used to eating so much less food.
Mignon: And you do feel better.
Adam: But it's hard to get there, because it takes a couple of weeks to get to that zone, and then you can totally lose it when you go out to dinner with people, es[especially around the holidays and whatnot, because it's really hard to not eat when you are around people who are eating.
Mignon: Right. And you've got the stuffing, and the gravy and the potatoes...
Adam: And cookies.
Mignon: I have a program called FitDay that you can enter your food in and it shows you not only your calories, but also the nutrition that you are getting from them. And I've tried to get the US RDA of every nutrient just through my diet, and it's next to impossible. I've never been able to hit the 100% of US RDA of every vitamin and mineral through my diet.
Adam: And another thing....if you actually wanted to eat the food pyramid...
Mignon: It's like 4000 calories (laughing).
Adam: Right. It's at least 4000 calories (laughing).
SUMMARY
Mignon: To sum up though, obesity is a growing problem in developed nations, and it's even impacting the medical care that patients receive. But researchers are finding out a lot about ways to help people diet, and just the damage that fat can do, but how to get rid of it as well. There's a lot of promise, and a lot of hope, but still at the end of the day it's still up to the individual to regulate their own food intake, and get the exercise they need. It's hard. It's a life-long battle for a lot of people.
Adam: And we certainly encourage anyone to be hopeful about new development, but that the most important thing is to start acting today if you do have a weight problem, and go talk to your physician, maybe a nutritionist, and just try to eat healthy foods in reasonable quantities, and start doing a lot of exercise.
Mignon: Right. The basics are still the same.
