Resistance to Hormone Leptin Called Key to Obesity

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

By Jeffrey Perkel
HealthDay Reporter
Wednesday, March 7, 2007; 12:00 AM

Copyright © 2007 ScoutNews, LLC. All rights reserved.

WEDNESDAY, March 7 (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."