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Resistance to Hormone Leptin Called Key to Obesity

Study with mice could pave way to new drug therapies, researchers say

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HealthDay Reporter

WEDNESDAY, March 7, 2007 (HealthDay News) -- Researchers may have uncovered the biochemical defect that underlies food-induced obesity in mice.

Assuming it can be duplicated in humans, the finding suggests several potential anti-obesity drug targets, experts said.

Michael Cowley, of the Oregon National Primate Research Center at Oregon Health and Science University, led the study, which examined the cause of leptin resistance in diet-induced obese mice.

Leptin is a hormone, secreted by fat cells, which indicates how much fat is in the body and regulates food intake by binding to neurons in the hypothalamus region of the brain. In lean people, leptin serves to regulate weight by controlling appetite and the use of stored energy. Obese individuals, however, appear to be resistant to leptin, much as diabetics are resistant to insulin.

The question was, what is the mechanism driving leptin resistance.

In the study, genetically identical mice were fed a high-fat diet for 20 weeks, at which point about 65 percent were obese. (That's a finding that Cowley said highlights the importance of epigenetics -- genetic differences not coded in DNA itself -- in obesity).

By comparing the obese animals to their lean littermates, as well as to control mice fed a normal diet, the researchers found that leptin normally governs neuropeptide release from cells called neurons in the hypothalamus, suppressing food intake and controlling energy utilization. In animals made obese by diet, however, leptin failed to trigger any response in these cells.

"We knew these cells were leptin-sensitive already," Cowley said. "The interesting finding was that they become non-responsive. We've identified the site of leptin resistance."

The study is published in the March 2007 issue of Cell Metabolism.

Dr. Julio Licinio, chairman of the department of psychiatry and behavioral sciences at the University of Miami Miller School of Medicine, who was not involved in the research, praised the study, calling it "very rigorous and sophisticated."

Licinio cited two interesting implications of the research. The first is that, in mice at least, leptin resistance is what he calls "functional," not permanent, and can be corrected by diet-induced weight loss.

Said Cowley: "If we put the obese animals on a low-fat diet, they recover from leptin resistance and drop weight. And when they recover, all the circuitry responses return to normal. We don't know if humans would respond in the same way, but we know that weight loss in humans is beneficial, even if you don't hit the ideal target weight."

Licinio also said the study suggests potential targets for drug development to fight excess weight. But, he added, "What the paper does not show is how resistance occurs and how you can overcome it."

One interesting facet of the findings, Cowley said, is the recognition that obesity, like diabetes, is truly a physical disease. "Obesity is not just a failure of will," he said. "This is a fundamental biological difference between obese and lean groups."

Licino said: "I think the take-home message is that (this study) gives hope. You need the caveat that it's not the same between mice and humans, but it does give hope that loss of a person's (ability) to regulate what they eat can be restored to maintain a normal weight."

More information

For more information on obesity, visit the U.S. Centers for Disease Control and Prevention.

SOURCES: Michael Cowley, Ph.D., assistant scientist, division of neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Ore.; Julio Licinio, M.D., professor and chairman, department of psychiatry and behavioral sciences, University of Miami Miller School of Medicine; March 2007 Cell Metabolism

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