Hormone links malnutrition and immunity.

When scientists first described leptin in 1995, they told a simple story: The hormone, secreted by fat cells into the blood, travels to the brain, where it signals how much energy the body has stored, and so leptin regulates appetite.

Leptin does more than just talk to the brain, however. In the Aug. 27 NATURE, researchers report that certain immune cells respond to the hormone. Its effects on the immune system may help explain why malnourished people are so vulnerable to infectious diseases.

Robert I. Lechler of Imperial College School of Medicine in London and his colleagues recently began to wonder whether leptin influences the activity of immune cells. "The logic behind the question was the long-established link between malnutrition and immunodeficiency," explains Lechler. At the other extreme, he adds, mice that are obese because of an inability to make leptin or to respond to it also possess an impaired immune system.

In initial test-tube experiments, the researchers found that leptin increases the ability of helper T cells, one class of immune cells, to proliferate after being stimulated into activity. The scientists then established that such cells indeed have leptin receptors, surface proteins that allow a cell to respond to the hormone.

Further experiments by Lechler's group suggested that leptin modifies the type of response the helper T cells make. Leptin encouraged helper T cells to make a socalled Th1 response, marked by secretion of chemicals such as interleukin-2 and interferon-gamma, rather than a Th2 response, which releases other interleukins.

Through the chemicals they secrete, helper T cells guide the actions of the immune system. For example, they may rally immune cells that fight off viruses or instead summon cells that defend against fungi and various bacteria.

To confirm that the test-tube experiments reflect a true immunological role for leptin, the scientists also studied the hormone's influence on the immune system in live mice. When mice are starved for 48 hours, which significantly reduces the amount of leptin in their blood, their T cells normally become much less responsive. Yet when the researchers administered leptin to mice while depriving them of food, the animals showed no T-cell impairment, even though they still lost weight.

Why would a hormone secreted primarily by fat cells regulate the immune system? "The best model of how leptin works is that it is a signal of starvation or malnutrition so that [the body knows when to] shut down energy-expensive functions," notes Lechler. For example, women with little body fat, such as marathon runners and ballet dancers, often cease their menstrual cycles, apparently because the body has interpreted the lack of leptin as a signal to avoid reproduction. Similarly, Lechler speculates, falling leptin concentrations in the blood may instruct the body to suspend temporarily the actions of the immune system.

The researchers are now testing whether administration of leptin can prevent malnourished mice from suffering an increased rate of infections. The results might indicate whether leptin could serve as an immune system booster for low-birthweight babies or people with AIDS or cancer, who often experience a wasting syndrome.

Ranjit K. Chandra of the Memorial University of Newfoundland in St. John's, who studies the impact of nutrition on the immune system, notes that nutritional disorders such as malnutrition bring about extensive metabolic and hormonal changes. "It's unlikely that a single one would be the key to all the immunological problems," he cautions.

"I wouldn't go so far as to say that [leptin] is likely to explain the entire immune collapse that occurs in patients who are severely malnourished, but it may be the biggest element," comments immunologist Terry B. Strom of Beth Israel Deaconess Medical Center in Boston.