Researchers Link Obesity to Hormone

OHSU scientists and others discover leptin affects the hunger-controlling nerve cells 

ANDY DWORKIN / The Oregonian 2apr04

Shortages of a hunger-limiting hormone called leptin seem able to change the growing brain of infants in ways that may dispose them to childhood or adult obesity.

In children and adults, the hormone alters the connections that specialized hunger-controlling nerve cells in the brain make with other cells, say two studies in today's journal Science—one by Oregon Health & Science University workers. The research indicates that some obese people are biologically different, because nerve connections send signals to the body as cables carry messages in machines. It may also help explain why a person's body tends to maintain a certain weight or "set point," like a thermostat.

The studies on mice and cells do not immediately point to new treatments for obese people. Although doctors treat a few weight-related conditions with leptin, the hormone disappointed many scientists with its very modest effect on many overweight people.

But knowing more about how the brain builds and runs its weight-control system probably will advance quests to discover how obesity forms and where doctors might disrupt that process.

"I would be very optimistic," said Dr. Jeffrey Friedman, a Rockefeller University scientist who wrote one of the new papers and who helped identify leptin 10 years ago.

Obesity is an urgent topic in the United States, where fat and poor fitness are poised to pass smoking as the leading preventable cause of death. The U.S. Centers for Disease Control and Prevention estimates that poor diet and fitness kill about 400,000 U.S. residents a year, mostly through diseases linked to excess weight, such as heart attacks, strokes and some cancers. Nearly a third of U.S. adults are now obese, up from 13.3 percent in 1960.

Scientists debate whether genetics or environmental changes are behind the obesity boom. But OHSU researchers' new paper supports a third idea: Conditions in the womb can affect fetuses, programming people for obesity.

The researchers with OHSU's Oregon National Primate Research Center studied a mysterious spike in leptin levels that washes over developing infants. It seems to hit humans in the last three months before birth, said Richard Simerly, a study author with fellow primate center scientists Shin Draper and Sebastian Bouret. The leptin surge comes the week after birth in mice, the animals the OHSU trio studied.

Using fluorescent molecules that track cell growth, the OHSU scientists watched nerve cells develop mice with a genetic mutation that limits their leptin supply. They focused on nerve cells that grow deep in the brain, some of which send signals of fullness when stimulated, others of which send hunger messages.

A lack of leptin discouraged those nerve cells from sending out axons—snaky arms that grow to carry nerve signals to distant brain regions. At 10 days old, the mutants' nerve cells had sent just a tenth as many axons out to two hunger-regulating brain areas as the normal mice. Even as adults, normal mice had three to four times as many of these connections.

The researchers could make the mutant mouse brains look normal by giving them leptin injections. But that only worked on very young mice, at the age where the leptin surge normally hits. Leptin shots did reduce the appetite of adult mice but did not alter the permanent changes to their brains.

"What we've identified is probably one factor that contributes to a developmental phenotype of obesity," or tendency to become obese, Simerly said. He added that "obesity is a very complex process" with many causes.

The study adds leptin to a list of hormones, including estrogen and testosterone, that help wire the developing brain then return in childhood and adulthood to influence those same brain regions, he said.

Humans rarely have two deficient copies of the leptin gene, as the mutant mice have, scientists said. But other genetic or environmental factors probably cause more modest leptin shortages in some developing animals.

The Oregon research bolsters arguments that conditions in the womb might influence leptin levels and brain wiring. For instance, evidence shows that mothers who are either underfed or overfed at key points of pregnancy bear children that are prone to become obese.

"What this paper does is put neonatal development on the map" by showing it alters brain circuitry, said Dr. Jonathan Purnell, an OHSU obesity expert not involved in the new study. "This particular study, I think, has important implications for public health policies" promoting good nutrition in pregnant women.

While the Oregon scientists looked at the output of hunger-regulating nerve cells, Friedman's group studied connections feeding information into those same cells. Compared with normal adults, the mutant mice had about four times as many nerve connections, or synapses, turning on their hunger-stimulating neurons. They had about three times fewer synapses turning on the neurons that signal fullness.

Injections of leptin changed that situation dramatically. Within six hours, the injections altered the connections to the key nerve cells in the obese mice. After a few days of leptin treatment, the mutant mouse brains looked like normal ones.

Friedman said leptin's rapid rewiring of the brain looks like "a key means by which changes in nutrition are communicated to other body systems."

The rewiring also offers a biological explanation for the theory of set points—that people have a weight their body tries to maintain, within 10 or 15 pounds. While the rewiring might make it sound easy to change a set point, Friedman said it actually may serve to protect that point: The brain will change its wiring to maintain a given body weight. That could help explain why consistent weight changes are so hard to maintain, he said, though more research is needed to explore the set point theory.

If scientists can find ways to cause that rapid rewiring, or freeze the wiring machinery of lean-running brains, they might be able to help control weight, said Tamas Horvath, a Yale University expert who worked with Friedman on the paper.

source: http://www.oregonlive.com/printer/printer.ssf?/base/front_page/1080910876297910.xml 2apr04