Team Discovers Mouse Appetite Suppressant

By Mark Schrope

A protein called interleukin-18 (IL-18), previously known mainly for its role in the immune system, is also a powerful appetite suppressant for mice once they reach the equivalent of adulthood, according to scientists at The Scripps Research Institute. Members of the research team hope the work will eventually lead to the development of new treatments for preventing obesity in humans. Unlike similar proteins, IL-18 suppresses appetite without unwanted side effects such as fever or sickness behavior, suggesting it might be a particularly good target for further study.

The research, led by Eric Zorrilla and Bruno Conti, both from The Scripps Research Institute, was published June 19 in an advanced, online edition of the Proceedings of the National Academy of Sciences (PNAS).

Until now, interleukin-18, a proinflammatory cytokine, has been the focus of research in a number of laboratories because the protein plays a role in stimulating the immune system. This is the first time absence of the protein has been linked to overeating and subsequent weight gain.

In fact, the Scripps Research scientists discovered IL-18's appetite suppressant activity after noticing that mice that lack the gene that produces IL-18 (known as IL-18 "knockouts") eventually become obese. "We were a bit surprised and skeptical at first," says Conti, "because we wondered why nobody had seen this before."

Further investigation, however, showed that the effect had been hidden by time. The mice begin to gain extra weight only later in life, around the fifth month of life, beyond the age range of previous studies.

Once obesity in older IL-18 knockouts had been discovered, the scientists set out to determine if IL-18 was controlling appetite directly, or if its absence caused obesity by some other mechanism. To shed light on this question, the scientists carefully tracked the feeding habits of normal and IL-18 knockout mice throughout their lifespan, finding that that IL-18 knockouts did in fact begin overeating before the onset of obesity—results that suggest IL-18 is an appetite suppressant. Interestingly, overeating was more pronounced when the mice ate a diet high in carbohydrates than when they were fed a diet high in fats.

The knockout mice also processed the food they ate more efficiently, storing more fat per unit energy that they ate. Knockout mice tended to spare body fat as a fuel source, and females that lacked IL-18 had lower than normal rates of metabolism. "The knockouts are getting it from both ends," says Zorrilla. "They're overeating, and their energy expenditure is low." As a result, the IL-18 knockouts developed substantial fat deposits, two to three times larger than those of normal mice.

Conti and Zorrilla note that on one level it makes sense to find molecules tied to the immune system that also control appetite, as appetite loss is a common symptom of illness. Recent studies also indicate that many molecules that modify immune responses also play a normal role in regulating body fat, outside of illness. One promising aspect of IL-18 is that the protein does not seem to cause fever or aversive symptoms that would be undesirable in a treatment for obesity. In contrast, some similar, previously discovered appetite suppressants, such as IL-1, do have such side effects.

In another finding of the study, the Scripps Research team showed that IL-18 had roughly the same suppressive impact on food intake of hungry mice whether the protein was injected into or outside of the brain. This could be especially important should a molecule that mimics IL-18 prove useful as a treatment, potentially simplifying administration.

A number of questions must be answered, however, before IL-18's therapeutic potential can be ascertained. To that end, the Scripps Research scientists are exploring the biochemical basis of IL-18's appetite suppression, as well as questions related to its specific effects on feeding. Another open question is whether obese individuals would respond to IL-18 therapy, because there may be desensitization to IL-18 with this condition.

In addition to Zorrilla and Conti, authors on the PNAS paper, titled "Interleukin-18 controls energy homeostasis by suppressing appetite and feed efficiency," are Manuel Sanchez-Alavez, Molly Brennan, Rosette Fernandez, and Tamas Bartfai, from Scripps Research, and Shuei Sugama, from the Nippon Medical School in Tokyo. See PNAS.

The research was supported by the National Institutes of Health and the Ellison Medical Foundation.

Send comments to: mikaono[at]scripps.edu

"The knockout [mouse models] are getting it from both ends. They're overeating, and their energy expenditure is low," said Assistant Professor Eric Zorrilla.

"We were a bit surprised and skeptical at first because we wondered why nobody had seen this before," said Associate Profrssor Bruno Conti.