Mice with mutation feel the burn

Without immune gene, rodents in a new study make heat not fat

September 3, 2009 at 2:01 pm

Mice with a mutation in an immune gene don’t get fat, they burn it.

RESISTING WEIGHT GAIN Two mice were fed high-fat diets for several months. But the mouse on the left, genetically engineered to lack an immune system gene, put on less weight than the mouse on the right. Scott Galvin, University of Michigan Photo Services

A gene that helps regulate inflammation also stops fat cells from wasting energy. When the gene, called I kappa B kinase epsilon or IKKε, is missing, mice turn a high-fat diet into heat instead of body fat, a new study in the Sept. 4 Cell shows.

If the gene works the same way in humans as in mice, it could be a new target for antiobesity drugs.

Scientists previously learned that low-level inflammation produced by obesity could trigger type 2 diabetes. But the details of the connection are still unclear, says Alan Saltiel, a cell biologist and endocrinologist at the University of Michigan in Ann Arbor. In the new study, Saltiel and his colleagues fed mice a high-fat diet and discovered that levels of IKKε were elevated in the liver and fat tissue of the mice, compared with mice on a regular chow diet. IKKε is known to be involved in regulating inflammation, and the researchers thought the molecule might be the link between diet and diabetes that they were looking for.

“What I expected was that if we knocked out this gene we’d get rid of the link between obesity and diabetes,” by eliminating inflammation, Saltiel says. He didn’t suspect that the connection would be severed further up the chain — preventing mice from getting obese in the first place.

IKKε is a largely overlooked member of a family of four kinases known to be involved in inflammation, says Gökhan Hotamisligil, a professor of genetics and metabolism at Harvard University Medical School in Boston. Researchers have paid more attention to IKKε‘s siblings IKK± and IKKβ, but those two forms don’t become more active in fat cells, or adipocytes, in response to obesity. Yet drugs that inhibit all the IKK kinases improve inflammation and symptoms of diabetes, leaving researchers with a mystery about which form of kinase forges a link between obesity and disease.

“For quite a while we had gaps in the understanding of how adipocytes promote inflammation,” Hotamisligil says. “This study sheds some light that IKKε could be tipping the balance in adipocytes,” causing the fat cells to release inflammatory chemicals.

Mice lacking the gene increase production of an energy-burning protein called uncoupling protein or UCP1, the researchers discovered. The protein is found in mitochondria, the power plants of the cell. Excess UCP1 causes fat cells to burn more energy and release it as heat, akin to an incandescent light bulb that sheds heat along with light.

Normally, IKKε “keeps the brakes on the expression of UCP1 in white fat,” Saltiel says. “When we knocked out IKKε, we released the brakes.”

After three months on a high-fat diet, the mice with the mutation gained an average of 12 grams, while normal mice gained about 20 grams. Both types of mice on a normal diet weighed about 32 grams on average. Although the mutant mice still gained some weight, the researchers say that it wasn’t enough to trigger the inflammation and diabetes associated with obesity.

It is clear that removing IKKε changes the mice’s energy balance, says C. Ronald Kahn of Harvard University Medical School’s Joslin Diabetes Center in Boston, but the mechanism for the change still isn’t understood. Kahn suspects that the mutant mice have more energy-burning brown fat cells, which are rich in UCP1, mixed in with white fat.

The researchers think that IKKε works mainly in fat and the liver, but since this study removed the gene from every cell in the body, the team cannot be sure where the gene exerts its influence most strongly, says Philipp Scherer, director of the Touchstone Diabetes Center at the University of Texas Southwestern Medical Center at Dallas. “These improvements could be secondary to improvements in other tissues,” he says. It will be important to know which tissues are affected if drugs that suppress IKKε are developed for use in people.

Previous studies have shown that mice lacking the immune gene are more susceptible to deadly viral infections. But Saltiel says that potential drugs inhibiting IKKε to fight obesity probably wouldn’t turn the gene off completely, leaving enough activity to combat infections. White blood cells from the mutant mice in the new study responded normally to a substance designed to mimic a bacterial infection.