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Leptin, the Appetite Hormone, Rewires the Brain

By Nancy Touchette

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Mice without the leptin gene are morbidly obese (right) compared to normal mice (left).
Researchers have discovered that leptin, an appetite-suppressing hormone, works in an unexpected way. The hormone, which has attracted considerable attention as a potential key to weight loss, is produced by fat cells, but it controls hunger by acting on the brain. Now, two new studies in mice show that the hormone works by actually rewiring the neural circuits in the brain.

The research also shows that some of these circuits are set just after birth, presenting the possibility that, at least to a certain extent, the tendency to overeat and gain weight may be hardwired early in life.

Although the new studies were conducted in mice, researchers believe the research may help them understand human obesity because the hormone has the same effect in humans as in mice. Like mice, people who are missing the leptin gene become morbidly obese. But when these rare individuals are given leptin, they lose weight.

Most obese people are not missing the leptin gene and are known to produce leptin. In fact, some have more than enough. Researchers believe that obesity may be caused, in part, by defects in the signaling pathways in the brain that normally respond to leptin.

“We decided early on that the leptin story was going to very complicated,” says Jeffrey Friedman of Rockefeller University in New York City, who led one of the studies. “To move ahead, we have to understand how leptin acts normally and which of its effects are missing in obese individuals.”

Leptin promotes the growth of mouse neurons. Images show growth patterns without leptin (top) and with leptin.
The findings surprised researchers, who thought that leptin worked by activating individual neurons, not by changing the way they connect to each other.

“You can imagine that information flows between neurons much like water through the plumbing system in a house,” says Friedman. “You can regulate this flow by opening and closing valves, or you can add or subtract pipes from the whole system.”

“We thought leptin would act by opening and closing valves. Instead, it appears to add and subtract pipes,” he says.

In the new study, published in Science, Friedman, in collaboration with Tamas L. Horvath at Yale University School of Medicine in New Haven, Connecticut, found that mice without the leptin gene have more connections coming into neurons affected by leptin than do other mice. The result was more circuits that increase appetite—and fat mice.

But when the mice were given leptin, the circuitry was reversed. The mice developed normal neural connections, and normal appetites.

In a second study, also appearing in Science, researchers noted that shortly after birth, both mice and humans experience a surge in leptin levels. This seemed perplexing because leptin normally signals appetite suppression. But newborns need to eat more, not less.

“People didn’t understand this leptin surge,” says Richard Simerly of the Oregon National Primate Research Center in Beaverton, who led the second study. “But we wondered if it was acting as some sort of developmental signal.”

Simerly and his colleagues found that in mice without the leptin gene, the neurons that normally respond to leptin fail to project to other regions of the brain involved in food intake—and the mice become fat.

When Simerly gave the mice leptin immediately after birth, all the neural circuits that control food intake formed normally and the mice maintained normal weight.

However, if the leptin-deficient mice were not given leptin until adulthood, the circuitry was not restored and the mice remained fat.

“We were stunned by this result,” says Simerly. “It told us that leptin acts as a developmental signal that determines the circuits that it acts on later in life.”

Taken together, the two studies suggest that leptin affects two distinct types of neural connections at different times. Early in life, leptin guides output from neurons that affect appetite. Later, leptin signals the input to these same neurons.

Researchers still don’t know what causes the surge in leptin during development or whether it is affected by early feeding habits. If leptin release in early life is influenced by nutrition, this period could be critical in future weight control.

It’s not yet clear whether the neurons that affect appetite in mice work the same way in humans. But the studies raise the possibility that leptin affects the wiring of a brain circuitry that influences an individual’s weight for life.

“I wouldn’t exactly say that leptin dictates a ‘set weight’” says Simerly. “But in controlling the kinds of neural connections that are made in the brain, leptin may be one of the factors that determines the range of weights a person is likely to have throughout life.”

Pinto, S. et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110-115 (April 2, 2004).
Bouret, S.G. et al. Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304, 110-115 (April 2, 2004).
Elmquist, J.K. and Flier, J.S. The fat-brain axis enters a new dimension. Science 304, (April 2, 2004).

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