Protein Key to Obesity Hormone's Effect on Brain
Thu Apr 11, 2002

By Keith Mulvihill

NEW YORK (Reuters Health) - Although the "obesity hormone" leptin can spur weight loss in laboratory animals, it's not very helpful for overweight humans, who actually have lost their sensitivity to the hormone and have extra-high levels in their blood, researchers say.

Now a new study in mice suggests that tinkering with a second substance, a signaling protein that appears to be active in the "appetite center" in the brain, might increase sensitivity to leptin.

The findings suggest that the substance, known as protein tyrosine phosphatase (PTP1B), might be a target for anti-obesity researchers, according to the report in the April issue of the journal Developmental Cell.

"With the increased incidence of diabetes and obesity, our study shows that one specific protein, PTP1B, when inhibited, leads to increased leptin action," said Dr. Michel Tremblay, of McGill University in Montreal, Canada.

"Leptin is an important modulator of energy metabolism and appetite (and) inhibiting PTP1B should promote a decrease in weight gain even in severe cases of obesity," Tremblay told Reuters Health.

Leptin is produced by fat cells as a signal to the brain to curb eating when fat stores are adequate. When it was first discovered in the 1990s, the finding was met with much excitement and the hope was that weight would just "melt away" if obese people were given leptin.

Unfortunately, it turned out that the situation in overweight humans was much more complex than it was in extra-large laboratory animals. Obese humans, it seems, had too much leptin, and no longer responded to the hormone properly.

In the new study, Tremblay and colleagues looked at the region of the brain affected by leptin, known as the hypothalamus.

They worked with two types of mice. One type lacks the ability to produce leptin and is thus extremely obese. The second type lacks PTP1B alone and is less likely than other mice to become obese when fed a high-fat diet. By breeding the mice, they were able to produce animals that lacked both leptin and PTP1B.

While mice that lacked only leptin gained the most weight, the researchers found that, at 12 weeks old, the mice that lacked both genes for leptin and PTP1B weighed 12% less compared with mice that lacked only leptin. This was true even though the mice consumed the same amounts of food, the authors report.

Interestingly, the researchers found that mice that lacked leptin but had one working gene for PTP1B (normal mice inherit one gene from each parent) displayed an intermediate weight gain between only-leptin-deficient mice and mice deficient in both copies of leptin and PTP1B genes. This finding, according to the report, suggests that "inhibiting half the levels of PTP1B may be sufficient to invoke some weight loss."

The researchers also found that a deficiency in PTP1B seemed to enhance sensitivity to leptin when it was administered to animals.

"Previously, how leptin signaling is turned off in the body was not well known," said Tremblay. "This study demonstrates that PTP1B is a direct regulator of leptin signaling in the hypothalamus. This supports nicely the important value of PTP1B as a target in both obesity and diabetes," he added.

In his interview with Reuters Health, Tremblay noted that several pharmaceutical companies are already busy at work trying to identify drugs that would make good candidates for inhibition of PTP1B in people.

"Our present study would certainly help these programs to move forward into the clinics for both diabetes and obesity treatments," he said.

SOURCE: Developmental Cell 2002;2:497-503.


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