How the Hormone Leptin Helps Regulate Appetite

Published: April 23, 2020

Narrator: Troy Fryer has less than two percent body fat. Although he looks extremely fit, it’s the of lack fat that makes his muscles stand out. With no padding on his face, his cheeks look sunken and his eyes are deeply set.

Jason Simon-Fryer: How far are you off that way?

Troy Fryer: The little bit of fat on my body is behind my eyeballs and on my liver, so walking around not having fat, it feels like constant needles are poking through the bottom of your shoe.

Jason Simon-Fryer: You know, some stand up all day and are okay with it; Troy is not. Because he has no padding on his feet, nothing in between his knees, there’s no comfort at all. It’s just unbelievable to watch him struggle.

Narrator: Troy was born with a normal amount of fat. But by age six, he began rapidly losing weight, despite having a voracious appetite.

Troy Fryer: I would go through two or three loaves of bread in one day, making 10 sandwiches at a time. So, I would keep eating and eating and eating, until it would hurt. And if I didn’t get that food, I would get really upset and really angry. I would rip doors off their hinges.

Jason Simon-Fryer: I actually sent him in for a psych evaluation, thinking that there was something wrong, because he couldn’t take the answer “No.” It’s like he was starving.

Narrator: By age nine, Troy was clearly ill. Doctors were shocked to find that his blood was full of fat and cholesterol, symptoms typical of obesity. It made no sense, until Troy was diagnosed with a genetic disease called lipodystrophy.

Elif A. Oral: We always think about thinness as something good, but, in generalized lipodystrophy, it’s beyond thinness. It’s actually, absolute lack of fat under the skin, so, the excess energy doesn’t have a place to go.

Narrator: And that’s why Troy was sick. With no fat tissue, excess calories collected in his liver, enlarging and inflaming it.

Jason Simon-Fryer: And when it got to that point of the doctor saying there’s nothing else we could do for you, Troy turned to the doctor and said, “So how and when am I going to die?”

Narrator: Salvation would come from the discovery of a mouse that also couldn’t stop eating. But unlike Troy, this mouse was fat, not thin. A genetic mutant from a breeding experiment, it was nicknamed O.B. for obese.

Jeffery Friedman: This mouse had a defect in a single gene. And the impact of that gene was a mouse that weighed three times normal and had five times as much fat and that overate voraciously. And genetics is very powerful, because what it tells you is that obesity has a biological basis. What that basis is required identifying the gene.

Narrator: Scientists began to hunt for the mutation that made the mouse obese, combing through the 2.5-billion letters of its genome.

Friedman: Think of it as an alphabet. You spell out letters of the genome. There are four letters, A, G, T and C. These spell out, indirectly, proteins, and a single spelling error can lead to a defective gene.

Narrator: In 1994, after a decade of work, Friedman and his collaborators homed in on a gene only found in fat cells.

Friedman: That was really the moment of a lifetime. I pulled out the film with some vague hope that maybe this would reveal something about the nature of the O.B. gene. And I looked at it. And in that instant, I knew that we had identified the gene that makes a hormone and that plays a very active role in regulating appetite, metabolism and probably other biological systems.

Rudolph Leibel: So, if you injected that hormone into the blood of an O.B. mouse, the mouse lost weight. It would completely cure the mutation of a O.B. mouse.

Friedman: And over the course of a few weeks, depending on the dose you give, they’ll look indistinguishable from a normal mouse.

Narrator: The hormone was named “leptin,” from the Greek word leptos, meaning thin. Its discovery transformed our view of fat and the biological forces controlling appetite.

Friedman: The O.B. mouse cannot see itself in a mirror and realize that it’s hugely obese. It thinks it’s starving to death, because this very critical hormone is not being made by the body. And the idea that a hormone produced by fat can control what you think about food in a very important way, this is a very radical notion.

Narrator: A normal fat cell produces leptin, which travels to the brain and signals the hypothalamus, a region that determines when and how much we eat. High levels of leptin tell your brain you have plenty of fat stored, but low levels tigger an alarm to eat.

And for those like Troy, who can’t make leptin because they lack fat, getting the hormone would be lifesaving.

Jason Simon-Fryer: The starvation was gone within three days of him taking leptin. We saved a lot of money. Troy went from eating what three people would eat, to eating what a normal person would eat in a day.

Troy Fryer: Knowing that I was full, I’m like, “Wow, this is amazing.”

Narrator: Leptin can’t cure Troy’s disease, but by curbing his hunger, it protects his liver.

Oral: Leptin does not bring the fat back. It just helps to deal with fat’s absence. Patients finally can take a deep breath that they’re full and they don’t have to worry about eating.

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