NOVA: Let's start by getting on the same page with terminology. How do you define obesity?
Michael Rosenbaum: Ideally, we would define obesity on the basis of health. Therefore, obesity would be the degree of fatness at which your current or future risk of disease is increased. That's the ideal definition, but it's not practical. Popular measures used to assess body fatness, like Body Mass Index, essentially define body fat in terms of the ratio of weight to height. This approach is not infallible. Body Mass Index or similar measures can label someone who is very muscular like Arnold Schwarzenegger as obese and incorrectly label someone who may be of low weight but has a very high, unhealthy percentage of body fat as being not obese.
Is obesity a genetic disorder or a behavioral one?
Clearly there are strong genetic influences on body fatness. But what's really inherited is the rank order of body fatness within the population you choose to live. If both your parents were 200 pounds, that does not mean that you are destined to be 200 pounds. If both your parents were heavier than 75 percent of their friends who had similar lifestyles, then you're likely to be at the 75th percentile for body fatness among people who have a lifestyle that's similar to yours. The quality of that lifestyle is up to you.
You could make an analogy using baseball players. Say you decided that there were too many home runs hit in baseball. Your plan might be to reduce the number of home runs by extending the right field fence of every baseball stadium in the country back another 20 yards. You would see a reduction in the number of home runs, but the rank order of home run hitters would not change very much. You would still have Mark McGwire at the top of the list, and you would still have the pitchers at the bottom of the list. Similarly, if we all suddenly had to walk up the first three flights of stairs we encountered every day, we would all probably lose some weight. However, if we lined up from thinnest to fattest, the order wouldn't change very much.
Would you go so far as to say we have an obesity epidemic?
It is an epidemic. The associated diseases that go with it are also epidemics. The prevalence of Type 2 diabetes, for example, which used to be called "adult onset diabetes," has increased tenfold in children over the past decade. When I was a pediatric endocrine fellow in the mid-1980s, only about two percent of new pediatric diabetics were Type 2. Now it's between 20 and 30 percent. So what was formerly called adult onset diabetes is now a pediatric disease. This increase exactly parallels the increasing prevalence of obesity among children.
Is something in our genetic makeup evolving to make us fatter?
It is not that our genetic makeup is changing to make us fatter. "Progress" has resulted in an environment in which many genetic tendencies that conveyed distinct advantages to our ancestors are no longer good for us. It was clearly advantageous for our ancestors to be fatter. They would be better able to survive the frequent periods of undernutrition that they were subjected to, and women would be more fertile and better able to breast-feed their children.
Over the past two decades, the percentage of the population that is overweight or obese has been increasing at the rate of about 20 to 30 percent per decade, which is astounding. This doesn't reflect substantial changes in our genes. Rather, it reflects the interaction of genes that were selected for over many, many, many millennia of human existence on this Earth that would favor the storage of excess calories as fat.
"Anybody who's ever lost weight will tell you that it's relatively easy to lose it compared to how hard it is to keep it off."
So it's things that we are doing—or not doing in the case of exercise—that have changed over time?
Yes. If our distant progenitors wanted breakfast they had to go out and hunt for it. It didn't come to them delivered on a plate filled with bacon, eggs, and a waffle. The genes that have been good for us throughout over 99 percent of human existence would have encouraged us to store calories as fat, eat food when it was available, and not waste energy when we didn't need to. That was fine when food was often scarce and we needed to spend most of our day working to get food. These genes become maladaptive in an environment that offers an unbridled opportunity to consume calorically dense foods and participate in a sedentary lifestyle.
Put simply, our ancestors had to work very hard to obtain enough food to eat. Now we have to work very hard to earn enough money to join a gym and get rid of the food we have already eaten.
A weighty challenge
Is it harder to lose weight or keep it off?
That's an excellent question. Anybody who's ever lost weight will tell you that it's relatively easy to lose it compared to how hard it is to keep it off. So the problem is really not losing weight; the problem is sustaining weight loss.
Well, when you try to maintain a reduced body weight, your body fights back. So, for example, if you were to lose 10 percent of your weight—and it doesn't matter if you're fat or thin, a couch potato or a trained athlete—the number of calories you'll require to maintain that reduced weight will fall by over 20 percent. That means that if you lose 10 percent of your weight to, say, about 150 pounds, you are going to require about 300 to 400 calories a day less to stay at that weight than someone who naturally weighs 150 pounds. Alternatively, you will have to increase the number of calories you spend exercising by 300 to 400 a day to stay at that weight.
"There has to be a whole new class of drugs called weight-maintenance drugs, designed to keep people from regaining lost weight."
There are numerous systems that act to oppose the maintenance of a reduced body weight: your nervous system changes, your hunger increases, your thyroid hormones change, and many other systems are altered in a way that favors the regaining of lost weight. This would have been very good for our ancestors, but it is not right for us.
We read a lot in popular magazines about drastic surgical weight-loss measures like gastric bypass. In such cases, does the body still want to regain the weight?
There are a number of studies looking at energy expenditure in people who've undergone various forms of gastric-bypass surgery. They vary somewhat in their results, but the general trend is that the same forces that oppose the maintenance of a reduced body weight in people who diet to lose weight are also evident in people who have had gastric bypass surgery, even two years out.
Learning from leptin
Your recent research on obesity has involved supplementing a biological compound called leptin. What is leptin?
Leptin is a key component in a regulatory system for fat that is naturally found in all of our bodies. The concentration of leptin in your blood reflects how much energy the body has stored as fat—much like the gas gauge in your car reflects how much fuel you have—and sends that information to systems throughout the body.
What did your study involving leptin aim to prove?
We hypothesized that a weight-reduced state—the period after a person has dieted and lost weight—is perceived by your brain as a state of leptin insufficiency. When you lose weight, the amount of leptin in your body falls. We knew from previous studies that if you lost 10 percent of your fat, the amount of leptin in your blood would fall by about 10 percent. Our idea was that the body reads this low leptin level as a signal to gain back the weight so that the "fat gauge" reads "Full."
So how did you test your hypothesis?
We wanted to give injections of leptin in relatively low doses to people who'd lost weight. We predicted that a lot of the metabolic opposition to keeping that weight off would then go away, because we had restored them to a state of what their brain perceived as leptin sufficiency. In the same way, you look at your gas gauge and decide you have enough gas for your trip. If you believe you have enough fuel, then the reaction of the brain is, well, this is nice, let's stay like this.
It was a small study, right?
Yes, we had just 10 subjects. We admitted them to the Columbia University Clinical Research Center, placed them on a liquid formula diet, did all sorts of studies, and had them lose 10 percent of their weight. We maintained them at that reduced weight and then gave them just enough leptin to bring their leptin levels back to about where they were before they lost the weight.
And what happened?
Well, we found that the leptin had very marked effects on the metabolic opposition to keeping weight off. When we gave people leptin, their energy expenditure went up, their thyroid hormones normalized, and various other things that had otherwise acted to favor the regain of lost weight basically went away. Their bodies were happy at reduced weights because the signal, leptin, was restored to what the brain considered to be sufficient levels.
"Obesity is the only disease other than drug addiction that I know of where your body resists the cure."
Will leptin help people lose weight?
Probably not. Your body doesn't seem to care too much if you raise your leptin level by becoming fatter. We would predict that leptin will help people keep weight off but may have little or no effect in helping them lose weight. In fact, studies have shown that leptin administration, even at higher doses than we used in our studies, has very little effect, if any, on body weight in lean and overweight adults who are at their "usual" weights.
So what are the implications of your study?
From a pharmaceutical standpoint, there are a number of implications of our study and other related studies involving leptin. Weight loss and keeping weight off, or weight maintenance, are very distinct processes. The drugs that are out there now act to increase your energy expenditure or decrease your energy intake to unnatural levels to make you lose weight. Because there are so many systems opposing keeping weight off, these drugs work only temporarily. There has to be a whole new class of drugs called weight-maintenance drugs, designed to keep people from regaining lost weight. I think that the pharmaceutical industry is starting to move in that direction.
So for you, drugs that help you keep weight off are more useful than drugs that help you lose weight?
The problem is that the system that regulates body weight is so strongly entrenched within us that drugs that help you lose weight only work for a limited time. Our bodies essentially work against us in obesity. It's the only disease other than drug addiction that I know of where your body resists the cure. Weight-maintenance drugs should be designed to make your body happy at a reduced weight, not to make you lose more weight.
So if I've lost a few pounds and I want to keep them off, can my doctor prescribe leptin?
No, there is a lot of work to be done before leptin, or any type of weight-maintenance medication, is ready for prime time. Our studies were investigations into the basic biology of human body-weight regulation. They provide the evidence or blueprints for approaches that might be taken to keep weight off. Leptin has not been subjected to the rigorous, long-term clinical trials that would be necessary to demonstrate that it is efficacious and safe in sustaining weight loss over long periods of time. There are a number of over-the-counter products, like leptislim or leptinal, with names that sound like they include leptin. In fact, they do not include leptin. Leptin is a protein like insulin and will not be effective if taken orally.
What's the next step in your research?
Well, the kind of work that we're doing now is to look at the molecular mechanisms that underlie the body-weight regulatory system. We'll look at the effects of leptin on skeletal muscle, and how it exerts influence over so many systems in our bodies related to weight. The results of these studies will have important implications for the type of exercise that might be recommended to keep weight off and the directions in which the pharmaceutical industry will go to develop weight-maintenance medications.