Obesity

OBESITY

PBS Airdate: October 3, 2006

NEIL DEGRASSE TYSON: Okay, we talked about bungee cords, that stretchy force that binds protons and neutrons. They're kind of like springs.

Of course, what's great about springs is their flexibility. With some effort, I can stretch it, or I can make it smaller, at least for a little while. But it always bounces back to a certain predetermined size.

Well, according to some researchers, people might be like this, too. No, matter how hard we struggle to lose weight, our bodies will keep bouncing back to about the same size. And as David Duncan reports, that size might be predetermined by our genes.

DAVID DUNCAN (Correspondent): We are what we eat. And as we eat more and more, many of us gain weight we'd rather not have. But for some people, like Teresa Godfrey, the compulsion to eat is a lifelong struggle.

TERESA GODFREY: I try and control it as much as I can, but there are days that I cannot control it. And I just eat and eat and eat and eat, and I don't know when I'm full, really. And I'm aware that I'm doing it, but I can't stop it.

DAVID DUNCAN: Since childhood, Teresa has faced ridicule, embarrassment and blame for being overweight. So has her only son, Jake.

TERESA GODFREY: Parents in the playground used to look over and look at me, because I'm big, Jake's big, and just, thought that we sat there all day and ate food, basically.

ELANA (Addenbrooke's Hospital): (I was just going to ask you a few questions.

SADAF FAROOQI (Addenbrooke's Hospital): Patients like Teresa and Jake, have had, really, a very tough time, from a very young age. They have often been blamed for being overweight and obese. And it's amazing how we fail to see that, actually, being overweight and being obese can be due to a biological reason, can be due to your genes.

DAVID DUNCAN: Suppose you could prove that for certain patients, it's not lack of willpower that causes obesity, but the lack of a chemical inside the brain which tells us to stop eating? That would be no surprise to Jeffrey Friedman, an obesity researcher at Rockefeller University in New York City. Friedman believes that for each of us, eating behavior is, to a large extent, hardwired by our genes.

JEFFREY FRIEDMAN: What makes some people weigh 350 pounds and other people 150 pounds? To a very large extent, those are genes. And each of us are, to a large extent, predetermined to be at a particular weight—some people heavy, some people thin, most people in between.

DAVID DUNCAN: So we have very little control over our weight... that there's a set point.

JEFF FRIEDMAN: The set point defines a range for each person, and people can operate comfortably within that range. But the further one wants to deviate away from the set point in either direction, the more difficult it becomes. So that if you're at your stable weight and you want to lose 50 or 100 pounds, it is very, very difficult over the long term.

TERESA GODFREY: I lost 35 pound in between eight and nine months—found it very difficult, but did lose it. But it went back on. As soon as you stop dieting, it just goes straight back on.

JEFF FRIEDMAN: For obesity, the evidence for a number of sources would suggest that it's 70 to 80 percent genetic, which is the highest hereditability that's been recorded, with the possible exception of height.

DAVID DUNCAN: Twenty years ago, Friedman began experiments to uncover the genetics behind the hunger drive, trying to discover why certain lab mice are born with such a compulsion to eat that they become almost too fat to walk. Then, in 1994, Friedman and his collaborators made a groundbreaking discovery: these obese mice lacked a previously unknown hormone which signaled the brain to stop eating. Friedman named it leptin, after the Greek word for thin.

JEFF FRIEDMAN: Leptin is a hormone, made by your fat, that circulates in the blood, that then sends a message to your brain reporting how much fat you carry at a given point.

DAVID DUNCAN: The five milligrams of leptin in this bottle are 10 times the amount that can circulate in our bloodstream, where it acts like a thermostat to tell the body if it's starving or if it has enough fat to survive. How it works becomes clear when you see an animal genetically altered to produce no leptin at all.

JEFF FRIEDMAN: You'll notice a few things about these animals. One, obviously this animal is a lot larger or heavier. That animal is moving around everywhere, and this animal hardly moves at all. The only difference between these animals is a defect in a single gene, the gene that encodes for this hormone, leptin.

DAVID DUNCAN: And how does this relate to humans?

JEFF FRIEDMAN: Humans have the same hormone. And when humans are lacking this hormone, leptin, as is this animal, they, too, become massively obese and eat more. It turns out that this animal, because it lacks leptin, never gets the signal that it has sufficient fat, and thinks it's starving. Now if you were to give this animal leptin injections—replace the leptin it can't make on its own—they eat less, they lose weight, their fat content goes down.

DAVID DUNCAN: Friedman's discovery created a sensation. Was this the Holy Grail for the overweight, a possible cure for obesity?

STEPHEN O'RAHILLY: I remember, precisely, the day I read the Friedman paper. And the hairs on the back of my neck stood up, because I thought, "My word! This is a real insight into how body weight is controlled."

DAVID DUNCAN: Unfortunately, when leptin injections were given to obese human patients, most of them did not lose significant amounts of weight. Still, Stephen O'Rahilly, director of the obesity clinic in Addenbrooke's Hospital, in Cambridge, England, believed that Friedman's discovery held an important key to human appetite, if he could understand how leptin worked.

STEPHEN O'RAHILLY: Leptin does something to the brain. It suppresses appetite; it does it through a series of steps.

DAVID DUNCAN: Once leptin reaches the brain, it turns off cells that increase appetite and turns on cells that decrease appetite, in a dual action that suppresses hunger. A central switching component in the leptin process is the melanocortin 4 receptor or MC4R, which receives and passes on the message to damp down hunger. If these receptors are altered by genetic mutation, their surface becomes malformed, unable to process the message to switch off appetite.

STEPHEN O'RAHILLY: It would be very difficult to be a patient with one of these mutations, try to get slimmer when your brain is screaming, "You are hungry. You must eat."

TERESA GODFREY: You're just ravenous, and you just have to eat. And you can't stop. Some days you can't stop eating, and you're on and on and on.

JAKE GODFREY (Obesity Clinic Patient): So you just eat anything, until you're just full up. And then you just...you regret it. It's like, it just takes over you.

TERESA GODFREY: Until you actually physically begin to feel sick. And then you think, "Well, why did I eat all of that food? Why? I didn't really want that. Why did I eat it?"

DAVID DUNCAN: Eight years ago, Teresa Godfrey came to the obesity clinic in Cambridge searching for answers.

SADAF FAROOQI: They have always known that there was some reason why they were always hungry. They have always thought there was some reason why they gained weight more easily than others. And effectively, what we're able to do, is to provide for them an explanation for that.

DAVID DUNCAN: The new scientific breakthrough is understanding the gene that codes for the MC4 receptor. Teresa's gene has a mistake that causes her receptor to grow incorrectly.

SADAF FAROOQI: When we actually look at the gene in the lab, what we find is one particular one of those building blocks is actually different. And that's enough to stop this gene making a receptor that works.

DAVID DUNCAN: Sadaf Farooqi extracted Teresa's DNA from a blood sample, and then put it through a process to isolate the gene that encodes for her MC4 receptor.

SADAF FAROOQI: And I think, when the MC4 is done, we need to think about which other genes might be relevant to these patients.

DAVID DUNCAN: This gene was then amplified and inserted into a living cell in Farooqi's lab, which then grows Teresa's receptor in a flask.

SADAF FAROOQI: And when it's in those cells, those cells can actually be grown up and can actually behave in the test tube as if they were in Teresa's body. So, essentially, in this flask are some cells which grow up and express Teresa's MC4 receptor on their surface.

We add the hormone that normally activates the receptor. So, basically, the hormone should dock on the receptor and give us a readout.

DAVID DUNCAN: A normal MC4 receptor reads out 100 percent; but Teresa's malformed receptor reads out zero.

SADAF FAROOQI: So Teresa's receptor is really non-functioning.

DAVID DUNCAN: Measuring Teresa's mutation has allowed the doctors at Addenbrooke's, for the first time ever, to use genetics to accurately predict how much a patient will eat.

SADAF FAROOQI: Basically what we can show is that the defect in a single gene, in a single molecule, and how it behaves in the lab determines the amount of food people will eat at a single meal.

ELANA (Addenbrooke's Hospital): Hi. I've got your lunch here, and you can have whatever you like.

SADAF FAROOQI: We find that a person who is of normal weight, and whose MC4 gene is working normally, might eat somewhere in the realm of about 4- to 500 calories, when allowed to eat freely. Teresa, and with Jake, in fact, they would eat probably two and a half or three times as much.

TERESA GODFREY: Dr. Farooqi phoned me and told me the results, and I cried on the phone, because I was just so relieved. I cried for Jake, not for me, more so than anything else.

STEPHEN O'RAHILLY: Jeff Friedman's discovery of leptin, in 1994, was a phenomenal catalyst to, not only my work, but the whole of the field. This was the first time that a real molecule truly was regulating body weight in mammals, and we went on, then, to show that obviously it was relevant for humans, too.

DAVID DUNCAN: How many people have this MC4 receptor problem, and how does it compare to other genetic disorders?

STEPHEN O'RAHILLY: Our best estimate so far is that around one in 1,000 people carry a mutation in MC4 and are obese. That means that, worldwide there'll be tens if not hundreds of thousands of people with this, with this disorder, so it's not, not by any means, rare, and it's certainly commoner than some well-known genetic disorders such as muscular dystrophy or cystic fibrosis.

DAVID DUNCAN: Do you worry, that people will look at this and say, "Aha, it's not the, you know, the Big Macs^®; it's, it's genetic."

SADAF FAROOQI: Clearly, if you eat fast food all the time, and are very sedentary, whatever your genetic makeup, you are going to gain weight. Clearly, if you have genes that predispose you to gaining weight, you'll gain even more. So it's always a balance of the two. I think even people who are overweight or obese and don't have an MC4 gene problem, they will have other genes that are contributing to them gaining weight very readily.

DAVID DUNCAN: Scientists are already identifying other genes that contribute to obesity. The hope is to create medications that can help people who have these genes maintain healthier weight. But until then, overweight people should try to maintain the lowest weight their biology will allow.

JEFF FRIEDMAN: People should do what they can to improve their health, and that would include being at the lower end of their range, exercising, eating a heart-healthy diet. So I think we need to focus on what we can do and improve health to the extent of our ability, but not criticize people because they can't lose hundreds of pounds. It's their biology that makes it difficult to lose those hundreds of pounds, not some personal failing.

TERESA GODFREY: When I found about the MC4R, it was a relief, a relief and a release, to know that actually, yes, it's not all my fault, and there's a reason for this happening to me. I'd just like to be as I am now. I've accepted who I am. If you would say to me would you rather win the lottery, or would you rather find out about MC4R, I would say MC4R any day. You can keep your money.

Obesity

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David Duncan

Correspondent www.davidewingduncan.net/

Sadaf Farooqi

Addenbrooke's Hospital

Jeffrey Friedman

Rockefeller University www.hhmi.org/research/investigators/friedman_bio.html

Jake Godfrey

Teresa Godfrey

Stephen O'Rahilly

Addenbrooke's Hospital www.clbc.cam.ac.uk/SOR/orahilly.html