The Facts on Leptin: FAQ

The truth about the hormone leptin and obesity.

From the WebMD Archives

It's been called the "obesity hormone" or "fat hormone" -- but also the "starvation hormone." When scientists discovered leptin in 1994, excitement arose about its potential as a blockbuster weight loss treatment. Even today, the Internet is loaded with sites that sell leptin supplements. Any truth to those pitches? And what exactly is leptin?

WebMD asked two experts on leptin to discuss how this hormone affects weight and appetite, as well as other aspects of health.

Q. What is leptin?

"Leptin is not our obesity hormone. Leptin is our starvation hormone," says Robert H. Lustig, MD, professor of pediatrics at the University of California, San Francisco and a member of the Endocrine Society's Obesity Task Force.

Leptin is a protein that's made in the fat cells, circulates in the bloodstream, and goes to the brain. "Leptin is the way your fat cells tell your brain that your energy thermostat is set right," Lustig says.

"Leptin tells your brain that you have enough energy stored in your fat cells to engage in normal, relatively expensive metabolic processes," he says. "In other words, when leptin levels are at a certain threshold -- for each person, it's probably genetically set -- when your leptin level is above that threshold, your brain senses that you have energy sufficiency, which means you can burn energy at a normal rate, eat food at a normal amount, engage in exercise at a normal rate, and you can engage in expensive processes, like puberty and pregnancy".

But when people diet, they eat less and their fat cells lose some fat, which then decreases the amount of leptin produced.

"Let's say you starve, let's say you have decreased energy intake, let's say you lose weight," Lustig says. "Now your leptin level goes below your personal leptin threshold. When it does that, your brain senses starvation. That can occur at any leptin level, depending on what your leptin threshold is."

"Your brain senses that and says, ‘Hey, I don't have the energy onboard that I used to. I am now in a starvation state,'" Lustig says.

Then several processes begin within the body to drive leptin levels back up. One includes stimulation of the vagus nerve, which runs between the brain and the abdomen.

"The vagus nerve is your energy storage nerve," Lustig says. "Now the vagus nerve is turned on, so you get hungrier. Every single thing the vagus nerve does…[is] designed to make you take up extra energy and store it in your fat. Why? To generate more leptin so that your leptin can re-establish its personal leptin threshold... It causes you to eat and it causes you to get your leptin back to where it belongs."

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Q. How does leptin affect weight

"Here's the question: If this thing works like a thermostat -- an adipostat -- why do we keep gaining weight?" Lustig says.

The problem is that overweight people have large amounts of leptin, but their brains aren't getting the important signal to stop eating.

"How come the brain doesn't get it? That phenomenon is called ‘leptin resistance,'" says Lustig, who has done research on the subject. Leptin resistance is similar to insulin resistance in type 2 diabetes, in which the pancreas produces large amounts of insulin, but the body doesn't respond to it properly.

Leptin levels can keep going higher as people get fatter. "We all have a leptin floor; the problem is, we don't have a leptin ceiling," Lustig says.

"In leptin resistance, your leptin is high, which means you're fat, but your brain can't see it. In other words, your brain is starved, while your body is obese. And that's what obesity is: it's brain starvation."

Not only is leptin part of the hunger system, it's also part of the reward system, Lustig says. "When your leptin levels are low, food is even more rewarding. When your leptin levels are high, that's supposed to extinguish the reward system so that you don't need to eat so much, and food doesn't look nearly as good."

But in leptin-resistant people, the reward system doesn't cue a person to stop eating when leptin levels rise, Lustig says. "The leptin is being made by the fat cells, the fat cells are trying to tell the brain, ‘Hey, I don't need to eat so much,' but the brain can't get the signal. You feel hungrier and the reward doesn't get extinguished. It only gets fostered, and so you eat more and you keep going and it becomes a vicious cycle. If your brain can't see the leptin signal, you're going to get obese."

Q. Can leptin work as an obesity treatment?

That was the great hope after leptin's discovery in 1994, says Richard Atkinson, MD, an endocrinologist, obesity expert, and clinical professor of pathology at Virginia Commonwealth University.

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According to Atkinson, mouse experiments that began in the early 1970s pointed to "some sort of a hormone that affected food intake and body fat, but [scientists] didn't know what it was."

When researchers finally discovered leptin in 1994, it helped "put obesity on the map because it suggested…obesity may have some physiological basis, instead of just being, "fat people can't keep their mouth shut,'" Atkinson says. "For those of us in the field of obesity, it was a watershed moment. Suddenly, everybody jumped on the bandwagon. This became a frantic obsession with the obesity community, at least."

Many scientists explored leptin as a possible treatment for obesity; they believed that if people were leptin-deficient, giving them leptin would raise levels, which would signal them to stop overeating. "But when you started giving it to people, it didn't work so well," Atkinson says.

"This stuff is made by fat tissue, and as you get fatter, you make more of it. That was quite a shock because everybody thought that obese people were going to be deficient in leptin," he says.

With the more recent understanding of leptin resistance, it makes no sense to give people leptin if they have an impaired response, Lustig says. "The resistance is still there. No amount of leptin is going to overcome that resistance."

Giving leptin only helps in a few extremely rare cases in the world in which people make no leptin at all, which causes them to overeat and become obese. When those people received leptin by injection, they stopped overeating and lost weight. But for the vast majority of people, the treatment won't work, nor is leptin approved as a medical treatment for weight loss.

"Leptin is still sort of experimental. There's no real need to take leptin now, unless you're one of those very small -- probably 100 people in the world -- who doesn't make leptin," Atkinson says.

Q. What about leptin supplements, such as those sold on the Internet?

Because leptin is a digestible protein that doesn’t enter the bloodstream, it can’t be taken in supplement form, Atkinson says. “If you were to take it as a pill, it’s just like eating chicken or beef. It’s a protein and your body would just break it up, so you wouldn’t absorb it from a pill.”

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So those “leptin supplements” sold on the Internet don’t actually contain leptin, even though their name can be misleading. Instead, these supplements contain ingredients that are purported to help improve leptin functioning or feelings of fullness.

“A variety of these supplements may be more aimed at total wellness -- things like helping balance other hormones, thyroid hormones -- just optimizing health so that the body begins to respond to leptin more appropriately and allows the person to feel full,” says Duffy MacKay, ND, a licensed naturopathic doctor who serves as vice president of scientific and regulatory affairs at the Council for Responsible Nutrition, a trade group for the supplements industry.

“Some of what you’re seeing is tried-and-true ingredients that are known to cause satiety, things like soluble fibers that have been known for a long time to help make people full,” MacKay says.

As for supplements’ effects on leptin functioning, the picture is less clear, he says. “The leptin science has only been unraveling since 1994, so there are a lot of unanswered questions.”

“No magic bullets are being discovered,” MacKay says. “[But] we shouldn’t write this pathway off as something that we shouldn’t continue to explore.”

Rather than taking supplements that haven’t been fully proven to help, overweight people have other options to aid leptin functioning, experts say. Lustig advises them to reduce resistance to insulin (a hormone that controls blood sugar) and to bring down high levels of triglycerides (a blood lipid).

“Insulin resistance generates leptin resistance. The practical advice is: Get your insulin down,” Lustig says. “How do you get insulin down? The best way is don’t let it go up. Sugar makes insulin go up. We are overdosed on sugar in this country. I think that if we got the sugar down, our insulin resistance would improve and that would help with the weight loss.”

Reducing high triglyceride levels helps, too, Lustig says. Too much triglyceride interferes with leptin’s journey from the blood to the brain via a leptin transporter that allows the hormone into the brain.

“When you’re insulin-resistant, you have high triglyceride [levels]. That’s one of the hallmarks,” Lustig says. “Triglyceride seems to block leptin transport into the brain. In order to make your leptin work, you have to let the signaling occur. The only way to let the signaling occur is to get your triglyceride down.”

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Q. Does leptin affect other parts of the body?

Leptin appears to have many functions that scientists are still exploring. "It didn't work as a weight loss agent, but there's now starting to be some other things that are really interesting about it," Atkinson says.

The hormone plays a role in heart and bone health, Lustig says. "We know that leptin is very important in keeping the immune system happy and that chronic inflammation occurs in the face of inadequate leptin signaling, and that's part of cardiovascular disease."

"We also know that leptin has direct effects on bone to increase bone health and bone mineral density, so when your leptin's working right, your bones are healthier and they accrue more calcium," he says.

Scientists are also finding some associations between leptin and certain cancers, Atkinson says. For example, some recent research suggests that leptin can promote the growth of melanoma, a type of skin cancer.

According to Atkinson, leptin may even affect women's fertility. "If the brain doesn't sense leptin, you won't be fertile. If you think back to our caveman days, when there were lots of famines, if you didn't have enough fat to survive a pregnancy, then you're better off not getting pregnant in the first place. Some people have thought that the leptin feeds back on the hypothalamus to keep the reproductive hormones working well, too."

WebMD Feature Reviewed by Laura J. Martin, MD on 1/, 010

Sources

SOURCES:

Richard Atkinson, MD, clinical professor of pathology, Virginia Commonwealth University.

Robert H. Lustig, MD, professor of pediatrics, University of California, San Francisco;  member, Endocrine Society's Obesity Task Force.

Ellerhorst, J. Oncology Reports, April 2010: pp. 901-907.

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