Fat Hormone Leptin Alters Brain Architecture And Activity, Which In Turn Drives Feeding Behavior

The research is published April 2 in Science. Studies were conducted by Shirly Pinto, Ph.D., and her colleagues Aaron Roseberry, Ph.D., and Hongyan Liu, Ph.D., postdoctoral fellows in the Laboratory of Molecular Genetics headed by Jeffrey Friedman, M.D., Ph.D., at Rockefeller, in conjunction with Tamas Horvath, D.V.M., Ph.D. and his colleagues at Yale University.

The Rockefeller scientists discovered that leptin acts by changing the wiring of the brain, a phenomenon known as plasticity. The hormone alters the wiring by controlling synapses -- the inputs and outputs to neurons that, in this case, regulate feeding behavior.

"This is a very dynamic effect that's quite dramatic and somewhat surprising," said Friedman, a Howard Hughes Medical Institute investigator. "In response to leptin, the cells create new connections."

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 are resistant to leptin's weight reducing effects. "The malleability of these feeding circuits by leptin suggest the possibility that the brain's wiring may be different in lean versus obese individuals," Friedman added.

In March 2004 the U.S. Centers for Disease Control and Prevention announced that obesity is now the second leading cause of death in the United States. Poor diet and inactivity now account for more than 400,000 deaths a year, second only to tobacco as a preventable cause of death.

Pinto and her colleagues have shown for the first time that leptin induces visible changes in the synaptic connections, and recordable changes in the electrical activity of specific brain cells.

Other researchers have shown that brain maps of cells can be quite plastic or changeable. 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," said Pinto.

For her research, Pinto used a famous mouse strain that resembles obesity in some humans. These mice lack leptin and grow to twice the size of a normal mouse with a body that contains five times the fat.

Using the obese mice, Pinto and her colleagues were able to show effects of the hormone on two particular sets of neurons: NPY and POMC. These neurons 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 colleagues discovered that leptin changes the number of connections that either excite or inhibit NPY and POMC neurons in the hypothalamus.

Led by Roseberry, the researchers also showed that leptin alters the electrical activity of the connections to NPY and POMC neurons. These effects are consistent with what the researchers found on the structural level.

In other words, leptin inhibits NPY neurons that encourage the animal to eat and reserve energy. At the same time the hormone 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.

The Rockefeller scientists suggest that these leptin-induced structural and functional changes are responsible for changes in the animal's behavior, too.

Six hours after administering leptin to obese mice, changes could be seen in their synaptic connections. Forty-eight hours later, they were eating less and at 12 days the mice had lost weight.

Finally, the researchers also discovered that the same brain wiring system could be influenced with a separate substance -- a peptide called ghrelin, found in the stomach and the brain. In contrast to leptin, ghrelin stimulates appetite. Application of ghrelin was associated with an increase in the numbers of inhibitory synapses on the POMC neurons, suggesting that the effects of ghrelin and leptin on the neuronal circuits may be evidence of a more general phenomenon regulating feeding circuits. But unlike leptin, ghrelin induced feeding behavior in minutes. Leptin appears to have a slower, more long-term effect, Pinto said.

Leptin was originally identified by Friedman and his Rockefeller research colleagues in 1994. He identified the gene that produces this hormone, which he named for the Greek word leptos or thin.

Other researchers have shown that leptin-deficient humans are massively obese and become lean with leptin treatment. Under Friedman's direction, clinical research on human patients is also ongoing at The Rockefeller University Hospital. Doctors are assessing the effects of leptin in overweight patients (who are not leptin-deficient) who follow a very low calorie diet.

Xiaoli Cai of Rockefeller University contributed to this paper, as did Sabrina Diano and Marya Shanabrough of Yale University.

This research was supported by the National Institute of Neurological Disorders and Stroke and the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.