The Johns Hopkins Gazette: July 3, 2000
July 3, 2000
VOL. 29, NO. 40


Mice's Weight Loss Is Researchers' Gain

Cancer-fighting prospect surprises scientists by turning off appetite

By Michael Purdy

Johns Hopkins Gazette Online Edition

Hopkins scientists announced last week that they'd created a compound called C75 that decreased appetite in mice and led to weight loss similar to that experienced during fasting. The compound's ability to work in humans has not been tested yet, but if it affects humans similarly, it could be a potent new tool for treatment of obesity and associated diseases such as diabetes, heart disease and cancer.

Lost in a rush of pressing concerns--how long do the effects last in mice? (a few days) are there any side effects? (none detected so far)--was a far more basic question: Where did C75 come from?

C75 came "out of left field," a place where no one really expected it to come from. Originally created as a potential cancer treatment, C75 took a curvy path to the headlines, from a chemistry lab at Homewood to a pathology lab at Bayview to a biological chemistry lab in East Baltimore.

Scientists involved in the research said C75's complicated history offers proof of one of the major benefits of large research institutions: Basic research often produces completely unforeseen benefits.

"This is an outstanding example of what can happen when an institution has many researchers exploring basic questions in a wide variety of specialties," says Craig Townsend, professor of chemistry. "You'll bump into someone in the hall working in another research area, mention your latest results, and suddenly a new and unexpected direction of investigation opens up."

Townsend's specialties include creating molecules that mimic the characteristics of naturally occurring organic compounds. He collaborates with Frank Kuhajda, a pathologist and biochemist at Bayview, who for more than 14 years has explored the connections between cancerous tumors and fatty acid synthase, or FAS, an enzyme the body uses to store extra energy in fat tissue.

Kuhajda discovered that breast cancers produced unusually high levels of FAS. Thoughts of using this characteristic as a way to test for cancerous tumors or to highlight them for therapy soon gave way to another idea: Perhaps a compound that suppresses fatty acid synthase could kill tumorous cells.

The idea paid off when Kuhajda showed that cerulenin, a known fatty acid synthase inhibitor, could kill tumor cells.

"They then asked me to help consider what could be done to design and synthesize better inhibitors of FAS," Townsend says. He made a series of compounds structurally similar to naturally occurring inhibitors as well as compounds designed on the basis of the mechanism of the biosynthetic reactions themselves. These were sent to Kuhajda for testing on mice genetically modified to grow human tumors.

An odd side effect soon became apparent: Mice treated with some of the compounds were eating less and getting dramatically thinner. This effect was most pronounced in mice treated with C75.

Townsend and Kuhajda had been consulting from time to time throughout their research with Dan Lane, biological chemistry professor and a leading expert on the regulation of appetite. When experiments suddenly started to produce reduced appetites, they knew it was time to ask Lane's lab to take a closer look at what C75 was doing to the mice.

Much of that work was completed by Tom Loftus, an instructor in biological chemistry and a member of Lane's research team. Loftus was the lead author on the paper on C75 in last week's issue of Science.

"Our area of expertise is adipose, or fat tissue, biology, and how that affects feeding," Loftus explains. Hunger and appetite may seem to come from the gut, but they are a combined product of systems in the gut and in the brain that use different cues to assess the body's need for food.

A key indicator for the brain is apparently the ratio of energy the body uses to the energy it stores in fat through FAS and other compounds. Higher rates of fat storage tend to lead to sensations of satiation and decreased appetite.

Loftus and Lane, along with Gabriele Ronnett, associate professor of neuroscience, found evidence indicating that C75 reduces production of a compound known as neuropeptide Y that helps indicate the opposite effect--lack of energy and a need to eat more food.

"We are not claiming to have found the fabled weight-loss drug," Kuhajda says. "What we have found, using C75, is a major pathway in the brain that the body uses naturally in regulating appetite, at least in mice."

A similar pathway is likely to exist in human brains, but scientists have no way of knowing yet if C75 will affect it.

The brain pathway affected by C75 is a particularly appealing target for researchers because it appears to be able to affect appetite without affecting metabolism. Fasting often causes the body to slow down its metabolism in response to reduced energy availability. This can make it even harder to lose weight.

"C75 may never be a useful drug," Loftus notes. "But even if it's not, it may help us learn enough about this pathway that we can design something useful based on that. The mechanistic aspects of how this drug works could end up being more important."

Whether C75 or a successor turns out to be helpful, the need for new treatments for obesity is great.

"Obesity is a huge public health problem," Kuhajda says, noting that it is epidemiologically linked to occurrence of other health problems including high blood pressure, heart disease and cancer.

The team of Hopkins scientists who studied C75 includes Loftus and Lane; Ronnett and Donna Jaworsky; Townsend and Gojeb Frehywot; and Kuhajda.

The study was funded by grants from the National Institutes of Health, Department of Defense, the W.M. Keck Foundation and the Steward and the Raynam Research Trusts.

Research is currently under way to further explore the effects of C75 and to lay the groundwork for possible human tests. Meanwhile, tests of C75 and other compounds as cancer treatments are also still under way, with some early signs of success.

"It just goes to prove what Louis Pasteur once said: Chance favors the prepared mind," Townsend says.