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How leptin rewires the brain
Study sheds new light on how the fat hormone works to control appetite
It’s been nearly 10 years since Rockefeller’s Jeffrey Friedman discovered leptin, a hormone found in fat tissue that’s critical to regulating weight. Yet despite a wealth of clinical data from patients who have undergone treatment with leptin in The Rockefeller University Hospital, scientists understand very little about how the hormone actually works.
Now, in research published in the April 2 issue of Science, Shirly Pinto, a postdoc in Friedman’s Laboratory of Molecular Genetics, has discovered that leptin affects both the architecture and function of neural circuits in the brains of mice, changing the brain’s wiring by controlling the inputs and outputs of brain cells that regulate feeding behavior.
Scientists know that brain maps of cells can be quite plastic. Pinto, whose scientific training is in the area of learning and memory, wanted to know if the same was true when it came to feeding behavior. “Feeding turns out to be a really good model to test plasticity because it’s much simpler to study than the system that controls learning or memory,” she says.
For her research, Pinto used a strain of mice that lack leptin; they grow to twice the size of normal mice and contain five times the fat. Six hours after administering leptin to these obese mice, changes could be seen in the synaptic connections between brain cells. Forty-eight hours later, they were eating less and in 12 days they were beginning to lose weight.
Two sets of neurons, called NPY and POMC, in particular were affected. Both are found in the hypothalamus, an area of the brain that controls appetite. NPY stimulates food intake and increases body weight while one of the active products of POMC, a peptide called alpha-MSH, has the opposite effect. Pinto and her colleagues discovered that leptin changes the number of connections that either excite or inhibit NPY and POMC neurons in the hypothalamus.
In other words, leptin inhibits NPY neurons that encourage the animal to eat and reserve energy and, at the same time, activates POMC neurons that curtail feeding. And it does this by altering the synaptic inputs of these cells — the points where the cells connect and communicate.
“This is a very dynamic effect that’s quite dramatic and somewhat surprising,” says Friedman, a Howard Hughes Medical Institute investigator and the university’s Marilyn M. Simpson Professor. “In response to leptin, the cells create new connections.”
In addition, the researchers showed that leptin alters the electrical activity of the connections between these neurons and the rest of the brain — not only does the structure of the brain change, but so do the patterns by which it operates.
Obesity is now the second leading cause of death in the United States, according to the Centers for Disease Control and Prevention in Atlanta, and it’s associated with more than 400,000 fatalities a year — second only to tobacco as a preventable cause of death.
Treatment with leptin reduces weight in some individuals but not in others. So learning more about the hormone’s mechanism of action could be critically important in understanding why some people do not respond to the hormone. “The malleability of these feeding circuits by leptin suggests the possibility that the brain’s wiring may be different in lean versus obese individuals,” Friedman notes.

May 14, 2004



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