By David N. Leff

What if there were a pill that took the place of physical exercise? Don't hold your breath - but stay tuned.

"We all reproach fat people," observed molecular and cell biologist Lawrence Chan, "for being lazy - eating too much, and not working it off by exercise. But we have to remember that one person may burn up the amount of fat he or she is accumulating much faster than the next person because of the difference in the rate of lipolysis - fat breakdown."

Chan, a clinical and research professor at Baylor College of Medicine in Houston, has identified a protein in the body called perilipin as "a very viable and exciting drug target for the treatment of obesity. It burns up energy," he explained. "What happens is, you break down your fat, and then the body resynthesizes it right away. So you have a futile cycle, and waste a lot of energy that way. You're spinning your wheels while doing nothing. So you actually waste a lot of the ATPs - all their energy is gone. That's why a drug target to inhibit perilipin can be thought of as a surrogate for exercise."

Chan is senior author of a paper in the December 2000 issue of Nature Genetics, titled: "Absence of perilipin results in leanness and reverses obesity in db/db mice."

"Perilipin works," he told BioWorld Today, "by coating the surface of fat storage droplets inside fat cells, thus protecting them from a fat-metabolizing enzyme called hormone-sensitive lipase (HSL)."

Perilipin, he recalled, was discovered by scientist Constantine Londos at the National Institute of Diabetes & Digestive & Kidney Diseases. The agency obtained U.S. patent No. 5,585,462, dated Oct. 4, 1993, protecting the protein. It claimed perilipin initially as a means of differentiating true adipocytes - fat cells - from other cells that mimicked them, owing to pathological changes.

"Ever since perilipin was reported," Chan pointed out, "there has been information from in vitro experiments indicating that the protein locates on the surface of lipid droplets in fat cells. A fat cell is nothing more than a big balloon of lipid with a nucleus on one side. Normally, perilipin stays on the droplet until a hormone - catecholamine, for example - stimulates its phosphorylation by ATP. That releases it from the droplet surface, at which point hormone-sensitive lipase - HSL - comes in. The lipid droplet becomes accessible to that enzyme, which then does its job of chewing up the fat as an energy source. But its normal action is kept in check by perilipin. In a way, perilipin acts as some sort of safeguard for the fat. It won't allow it to be degraded. It sort of puts a brake on that HSL enzyme."

Perilipin Knockout Mice Live It Up

Chan and his co-authors decided to knock that fat-guarding protein out from diabetes-prone db/db obese mice.

"We started off," he began, "with a murine embryonic stem cell [ESC], then screened the authentic gene for perilipin. Next, we introduced a mutation into that gene sequence to inactivate it, and injected the mutant ESCs into the ova of foster mice, where they developed to maturity. When we checked baby pups, many of them were missing perilipin.

"The extra calorie-burning capacity of the perilipin-free mice," Chan recounted, "was reflected in their metabolic rate, which was consistently higher than that of their wild-type cage-mates. Those perilipin-null mice stayed trim. For them, fat storage is a losing battle, because HSL metabolizes their fat as soon as they make it. This process burns a great deal of energy that would otherwise be deposited as fat.

"Those KO mice," Chan continued, "consuming 25 percent more food than normal animals, and - although leading a 'couch-mouse' indulgent life style - had only half as much body fat and 8 percent more muscle than their normal controls. I think that's very exciting," he remarked, "because very fat people often think, 'Well, if I'm genetically obese, there's nothing I can do about it.'

"But our in vivo experiments showed that if you can remove perilipin, you can actually burn up that fat. They demonstrate that lipolysis is an important factor in controlling body composition, and the amount of fat an individual accumulates. And we identified perilipin as a very viable and exciting drug target for treating obesity."

He continued: "We can conceive a drug that will inactivate perilipin, so that it's no longer a brake on the fat breakdown. There are several ways to do this. One is screening for some compounds that will turn off the activity of the perilipin protein. Another is to turn off its production, so there's less perilipin around, yet covers the same effect in terms of stopping HSL action."

Chan's lipid metabolism lab at Baylor is pursuing more basic perilipin research rather than drug development. "But," he observed, "there are many people who are interested. This is such new research, it hasn't been started yet. Baylor has filed a patent application covering our approach, and they are discussing the possibility of a license to this technology with potential licensees - talking to both pharmaceutical and biotech companies."

Perilipin's Fatty Built-In Safety Factor

Chan made the added point, "A drug such as we envisage might be better than some other targets that are expressed in every cell of the body, where the chance for adverse side effects is much higher. Whereas in our case, if some complication or whatever develops, it will likely be confined to the fat cells only.

"For example, some of the drug targets in the past worked in the brain. The brain is a pretty delicate tissue, so its chance of developing serious complications may be higher. Whereas if the drug target is produced only in fat cells you might get some problems there, but usually not serious."

Chan recalled that the slimming drug Fen-Phen had some effect on the cardiovascular endothelial cells - affecting the heart. That led to the adverse effects that might have required it to be withdrawn from the market.

"We hope," he concluded, "that perilipin inhibitors would be exempt from major complications - but I don't think we know yet."