Appetite control
Scientists still search for a pill to turn off hunger; a decade after learning how the body signals fullness
NEW YORK -- A decade ago this month, the world found out about the appetite-controlling hormone leptin, and suddenly a cure for obesity seemed within reach.
Drug companies raced to fashion leptin into a magic anti-obesity bullet. The public eagerly awaited a pill that would keep appetite in check for life.
Ten years later, though, obesity remains as vexing as ever -- and there's nothing remotely resembling a silver bullet. Leptin, a hormone secreted by fat cells to shut off hunger, has turned out to be far more complex than initially thought.
But a steady stream of insights over the years have illuminated leptin's complicated role within the body, and have made leptin therapy for weight gain once again a distinct possibility. Researchers now predict clinical trials on new leptin-related drugs will commence within two or three years.
The leptin story began in the pages of the July 28, 1995 issue of the journal Science. Rockefeller University's Jeffrey M. Friedman, who had a year earlier discovered the genetic roots of appetite control, published evidence that a hormone -- he dubbed it leptin from the Greek root leptos meaning ''thin" -- was the body's mechanism for signaling satiety.
Essentially, fat cells secrete leptin, which travels through the bloodstream to the brain's hypothalamus, the control center for hunger, thirst, sex drive, and other primal functions. When the body has stored enough fat, the hypothalamus is inundated with leptin, prompting it to stifle appetite and make us feel full.
Researchers -- many of them in Boston -- have also found evidence that leptin plays roles in reproduction and bone development, and perhaps many other areas. The full picture of how it interacts with the hypothalamus along these pathways is still emerging.
Other factors besides leptin also play a role in appetite, Friedman said during a recent interview in his New York City office. The stomach secretes another hormone, ghrelin, that stimulates hunger when the body needs energy. Smell and sight -- a piping hot pizza, for instance -- can stimulate appetite and cause overeating, as can cultural factors like food advertising and large portion sizes.
''But I think the biological factors are most potent," he said. ''Obesity is as genetic as height."
Along with
''Needless to say, after the discovery there was a barrage of interest in many companies," said Dr. Alex DePaoli, director of global development at the Thousand Oaks, Calif.-based drug company
Amgen quickly began human studies dosing obese people with leptin. Expectations were high. But the results were a severe disappointment.
''These studies showed that leptin had a biological effect . . . but that the magnitude of the effect was not one that would be considered clinically important in the general population," said DePaoli.
Amgen all but shut down its leptin clinical research program.
''Amgen rushed to do the clinical trials without having a clear idea of leptin's biology," said Beth Israel Deaconess Medical Center's Dr. Christos Mantzoros, whose lab has since published several key papers detailing leptin's biological effect.
But as researchers have made progress in understanding the hormone, targets for potentially new leptin therapies for obese people have emerged.
The key, as it turns out, may be coaxing the brain to listen to leptin.
Researchers had noticed that many obese people had leptin in abundance, yet their appetites went unchecked. It has now become conventional wisdom in the research community that these people are simply not sensitive enough to leptin -- somewhere along the molecular journey from fat cells to brain there has been a breakdown, and the hypothalamus does not know that the body has enough food to function.
Nearly 60 million Americans are obese, and up to 90 percent of them are thought to suffer from leptin sensitivity problems, Friedman said.
Leptin sensitivity has become a popular research area among endocrinologists, said researchers, and though the process is complex, several potential targets for drugs have emerged.
''We're about two or three years away from human tests," said Beth Israel's Dr. Jeffrey Flier, a lead researcher in the field.
Researchers have also been able to successfully use leptin for several non-obesity treatments. Many very thin women -- anorexics, athletes -- have such little fat that their menstrual cycles stop. Certain HIV patients develop bulging fat protrusions on their body, which leptin can stop. And a very few people -- only 15 have been identified in the world -- have a genetic defect that prevents leptin production, causing them to crave food 24 hours a day. Leptin therapy can quickly reduce their body weight by 50 percent, studies have shown.
Amgen has not let others use leptin for large-scale human trials since its initial failed experiments, though several leptin experts interviewed said the company has been actively talking to researchers about starting a new series of human trials.
Friedman and others believe that once researchers are able to pinpoint which obese people will respond to leptin sensitizing, drug companies will rush to develop drugs, given the potential market.
Friedman has won numerous awards for his leptin research, and has also become outspoken about discrimination against the obese, saying obesity is the ''only characteristic that people feel free to stigmatize."
But for all the social implications, potential profits and medical possibilities arising from his work, what still thrills him is that nature developed a hormone that connected body with mind to regulate that most primal need -- to eat.
''The most exciting thing," he said, ''was the realization that nature had solved the problem in a real elegant way." 