"Fat-Proof" Mice Yield New Anti-Obesity Drug Target

The Baylor researchers discovered the fat-protecting role of perilipin after breeding laboratory mice to eliminate the gene that codes for the protein. The team's findings appear in the December issue of Nature Genetics.

"Perilipin works by coating the surface of fat storage droplets inside fat cells, protecting them from hormone-sensitive lipase, HSL, a fat-metabolizing enzyme," said Dr. Lawrence Chan, a Baylor professor in the departments of medicine and molecular and cellular biology and lead investigator of the study.

But for perilipin-free mice, fat storage is a losing battle because HSL metabolizes fat as soon as it is made. "This process burns a great deal of energy that would otherwise be deposited as fat," Chan said.

The extra calorie-burning capacity of the perilipin-free mice was reflected in their metabolic rate, which was consistently higher than that of their wild-type cage-mates, said Chan. The mice also had eight percent more muscle and only about half as much body fat--despite consuming 25 percent more food and leading a "couch mouse" existence. And, while both groups of mice had the same number of fat cells, those of the perilipin-free mice were only half as large.

Being perilipin-free also benefited db/db mice, so named because they inherit the db gene that predisposes them to obesity from both parents. The mice, though genetically programmed to be obese, grew up lean after losing the ability to make perilipin.

"These results are very exciting because not only is perilipin active in humans, it is made almost exclusively by fat cells," Chan said.

The latter could be key to the success of new, anti-perilipin drugs designed to fight obesity. According to Chan, drugs that disrupt a very precise target like perilipin in body tissues have potentially fewer side effects than those affecting the brain or multiple organ systems.

Although he believes that perilipin research is very promising, Chan remains cautious. "This is an exciting first step, but it will take time to move perilipin research from experiments in mice to helping humans with weight problems," he said.

The study was funded by then National Institutes of Health, the USDA/ARS Children's Nutrition Research Center cooperative agreement, and the Sealy and Smith Foundation.