Flipping the Appetite Switch Off

From the WebMD Archives

June 29, 2000 -- While searching for a cure for cancer, a pathologist at Johns Hopkins Medical Institutions may have stumbled upon the solution to obesity. Puzzled when animals he injected with a compound called C75 lost weight, the scientist teamed up with other researchers to investigate why the mice in his lab weren't eating.

The multidisciplinary team discovered that C75 switched off a signal in an appetite-regulating pathway in the brain. A report on the discovery of this significant clue to obesity appears in the June 30 issue of the journal Science.

Frank Kuhajda, MD, the pathologist and a spokesman for the research team, says that when mice were injected with the C75, they stopped eating within 20 minutes, and they ate 90% less food over the next 24 hours. The effects diminished over a few days, but when mice were given a daily dose, their weight loss was profound. In fact, they lost more weight than fasting mice because their metabolism didn't slow down. Normally, when you fast, your body thinks it is starving and slows down its metabolism to compensate.

But "it will be years before something like this will make it to a bottle on your shelf for weight loss," says Kuhajda. While the mice had no side effects from C75, he says, the research must be done to prove the compound is not toxic to humans and that it has a similar action. "[It] will take a lot of work and require drug development," he says.

To obesity expert Louis Aronne, MD, director of the Comprehensive Weight Control Program at the New York Presbyterian Health Care Systems, this research is a major contribution to understanding obesity.

"The bottom line is that it shows we can understand the weight-regulating mechanism, and we will be able to control it," Aronne tells WebMD. He was not a member of the Johns Hopkins team.

C75 is a synthetic compound that inhibits an enzyme called "fatty acid synthase," which is involved in building fatty acids. Fatty acids are one form in which the body stores fat.

Prior to the Johns Hopkins team's research, it was thought that fatty acid synthase was only active in liver and fat cells. It was known to be present in the brain, but what it was doing there was a mystery. The researchers discovered that not only is the enzyme active in the brain, it may be indirectly monitored by the hypothalamus, the appetite center of the brain.

In a tricky chemical masquerade, the brain is fooled into thinking it's well fed. It seems that by inhibiting fatty acid synthase, C75 inadvertently causes an increase in the amount of another piece of fatty acid molecule called malonyl-CoA. Because malonyl-CoA mimics fatty acids, the hypothalamus detects no lack of fuel, and the mice don't feel hungry.

When malonyl-CoA builds up, Kuhajda says, "That may be signaling [the hypothalamus], 'Wow! You're really fed now. You don't need to eat anymore.'"

"This is very exciting, because it shows ... [how] the hypothalamus detects how much fuel is around. It makes a very persuasive argument that malonyl-CoA ... is that signal," says Aronne.

Aronne agrees with Kuhajda that this research is not likely to produce the magic bullet. "There are several overlapping mechanisms ... Ultimately, we'll need some sort of combined therapy for obesity with drugs on [different] sides of the feedback system ... between the brain and the fat cell," Aronne says.

Vital Information:

  • Researchers have stumbled onto a way to make mice lose weight -- with injections of a compound called C75.
  • The compound seems to work as an appetite suppressant by tricking the brain into thinking food intake hasn't changed, so metabolism doesn't slow down.
  • This new research has shed light on the way appetite is regulated by the brain, and researchers hope the findings will lead to new treatments for weight loss.