The discovery is another important clue about how leptin exerts its effects on the brain to cause decreased food intake and increased energy expenditure, said the researchers. The research also suggests that natural variability in the "wiring diagrams" of the neural feeding circuits of individuals may influence whether a person will be obese or lean.

The research team, which was led by Howard Hughes Medical Institute investigator Jeffrey Friedman at Rockefeller and Tamas L. Horvath at Yale University School of Medicine, published its findings in the April 2, 2004, issue of the journal Science.

Friedman and his colleagues discovered leptin in 1994. They also showed that it is produced by fat tissue and secreted into the bloodstream, where it travels to the brain and other tissues, causing fat loss and decreased appetite. In the brain, leptin affects food intake by acting on distinct classes of neurons in the hypothalamus that express the leptin receptor.

Leptin decreases feeding and fat deposition by acting on two classes of neurons. Leptin suppresses the activity of neuropeptide Y (NPY) neurons and it enhances the activity of proopiomelanocortin (POMC) neurons. Conversely, the absence of leptin increases feeding and fat deposition by exciting NPY neurons and suppressing the activity of POMC neurons.

While the action of these two types of neurons had been inferred, said Friedman, there had been no direct studies exploring the specific mechanism by which leptin affected the neurons.

"There are a number of theoretical ways in which a molecule such as leptin might modulate the activity of neurons," said Friedman. "And I'm sure it's the case that lepti
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
1-Apr-2004