Blocking enzyme helps fat-burning hormone fight obesity

October 25, 2005

GAINESVILLE, Fla. — Blocking an enzyme that prevents a fat-burning hormone from doing its job in people who are overweight could lead to a new way to treat obesity, University of Florida researchers have found.

UF scientists used vanadium, a trace mineral found in some popular diet pills, to block the enzyme PTP1B and enhance the helpful hormone leptin in rats, according to findings published recently in the online edition of the journal Endocrinology. In overweight people, this enzyme usually stops leptin from signaling the brain to burn energy and suppress appetite, leading to easier weight gain.

“The animals treated with the trace mineral plus leptin lost more weight and body fat than animals treated with leptin alone,” said Philip Scarpace, a UF pharmacology professor and the study’s senior author. “The reason they lost more weight is because leptin signaling was enhanced.”

Although high levels of vanadium could be toxic to humans, the study shows that stopping the enzyme could be a big step toward tackling the problem of leptin resistance, Scarpace said. The researcher’s ultimate goal is to develop an inhibitor that specifically blocks PTP1B, increases leptin function and is safe for humans.

The National Center for Health Statistics estimates obesity affects 60 million Americans. And leptin resistance and obesity go hand in hand, Scarpace said.

The hormone leptin is produced in fat tissue, so when a person’s body stores energy as fat, it also produces leptin. Typically, when leptin levels rise, a trigger is tripped telling the body to decrease hunger and burn food as energy. But when a person gains weight and there are continually high levels of the leptin in the body, this system shuts down, Scarpace said.

“If leptin does not work, you will become obese,” he said. “And what’s worse, once you become obese, your susceptibility to gaining even greater weight is increased. The more obese you are, the more difficult it will be to lose weight and the easer it becomes to gain more weight.”

This means that two people can eat the same size piece of chocolate cake and the overweight, leptin-resistant person would gain more weight than the normal weight person, Scarpace said.

“That’s why it’s important to figure out ways to reverse leptin resistance,” he said.

The leptin system also breaks down as humans age, which could explain why adults have a tendency to gain weight as they grow older, Scarpace said. And while there are a few people in the world who are obese because they are leptin deficient, all obese rats and nearly all obese humans have developed resistance to the hormone.

But finding ways to increase how much energy the body burns could be the key to conquering the obesity epidemic, particularly because it has been shown that most people cannot maintain long-term dietary restrictions, Scarpace said.

Obesity researchers see PTP1B as a potential target for future drug therapies, said Dr. Barry E. Levin, professor and vice chairman of the New Jersey Medical School department of neurology and neurosciences.

“Essentially, what that enzyme does is undo everything the leptin receptor has done,” Levin said. “The thinking has been that if you can inhibit that enzyme you will get more bang for your buck. The concept is a very good one.”

Hope for the leptin-resistant is not completely on hold, though. Cutting calories and losing weight can restore leptin response to normal, Scarpace said. But gaining weight starts the cycle again.

“Some aspects of obesity are out of our control, and it’s not fair,” he said. “Our bodies probably have a set point (for obesity) that is different from person to person.”