The Quest For The Antifat Pill Nature programmed us to overeat. Fen-Phen helped that, until it backfired. Safer drugs may be coming soon.
(FORTUNE Magazine) – If the number you see on the bathroom scale is even more depressing than your 401(k)'s bottom line, take heart. Dozens of slimming aids are in the pharmaceutical pipeline.
Over the past decade researchers have made a rush of discoveries about hormones and other molecules that regulate appetite and weight. That has provided a host of targets to tweak with drugs. But given the problems with past obesity drugs--remember Fen-Phen, the pill combination linked to heart damage?--one has to wonder: Will drugs ever seriously deflate the gross national girth without nasty surprises?
Maybe, but don't expect miracles. Consider leptin, the most acclaimed obesity drug candidate in recent years. A naturally occurring hormone whose gene was isolated in 1994 at Rockefeller University by Jeffrey Friedman and colleagues, it is thought to convey an "eat less" signal to the brain from burgeoning fat cells. When it was injected into congenitally obese mice, they quickly lost weight. But leptin performed much less impressively in human trials.
Another hormone, neuropeptide Y, also stirred excitement. It's a potent appetite stimulant, so drugs that block it seemed likely to suppress the munchies. Yet when researchers blocked NPY in mice, the rodents continued to show perfectly healthy appetites.
None of that surprises students of Darwin. Redundant mechanisms have evolved to ensure that fuel is conserved as fat to abet survival in lean times, says Eric Ravussin, who studies genes and obesity at Pennington Biomedical Research Center in Baton Rouge. When we push against the fat-conserving system by losing weight, it pushes back in multiple ways: Hormones scream to the hypothalamus, the brain's appetite-control center, "Eat! Eat inch-thick steaks and cheesecake!" Our metabolisms shift so a higher share of the calories we ingest get socked away instead of burned as fuel. Our muscles even become more efficient, according to some studies, forcing us to work harder to lose weight and keep it off.
Of course, most of us can beat this pushback for a while and shed tens of pounds. Recent data suggest that perhaps one in five who lose 10% or more of their weight manage to keep it off for at least a year, says Rena Wing, an obesity researcher at Brown University. But that kind of long-term success typically demands Olympic feats of will, such as religiously sticking to a low-calorie diet and exercising for an hour a day, notes Columbia University's Rudolph Leibel, an authority on the metabolic roots of obesity.
Leibel believes that an adult's weight is maintained at a "set point" programmed largely by genes. Just as a thermostat keeps room temperature fairly constant, our internal fat monitors switch on compensatory mechanisms when our weight varies much from the set point. A variation on this theme, called the settling-point theory, holds that super-rich diets can bump up the set point--which would explain why so many of us are getting fatter.
The thermostat analogy has major implications for research on obesity drugs. For instance, if scientists can unravel the feedback loop that puts us in fat-conserving mode when we lose weight, they might be able to interrupt it with medicines, making it a lot easier to keep lost pounds off. Surprisingly leptin, the apparent dud, may be one such medicine. In a small study published last spring, Leibel and colleagues showed that when leptin was administered to people who had lost 10% of their weight, hormonal signals associated with the body's fat-conserving mode were interrupted. Thus, even though leptin isn't effective for dropping pounds, it may help keep them off.
Amgen, the biotech company that owns rights to leptin, says it has no plans to test it as a weight-loss maintainer. But another medicine in late clinical tests, Axokine, may work in that role. Developed by Regeneron Pharmaceuticals in Tarrytown, N.Y., it activates the same metabolic pathways that leptin does, says CEO Leonard Schleifer. Unlike leptin, Axokine appears to help people both lose weight and keep it off. And its effect seems to linger, helping weight stay down even after doses are stopped. That prolonged efficacy worries some experts, though, for it suggests that the drug could have long-term side effects.
No single drug is likely to block all the mechanisms that kick in when we lose weight. Instead researchers envision treating obesity with combinations of medicines, each of which suppresses a different part of the fat-conserving system. Such cocktails could be tailored to body chemistry, promising long-term weight loss with minimal side effects.
That's still years away. Now we may be able to stimulate some of the desired hormonal effects with lifestyle changes, says Arthur Campfield, a Colorado State University researcher. For instance, obesity apparently causes the brain to become insensitive to leptin's "eat less" signal. But some studies indicate the insensitivity can be reversed by losing weight and exercising--so keeping off lost pounds may get easier over time. Indeed, research on weight, hormones, and the brain has made it ever clearer that obesity is basically a state of mind--and we don't necessarily need drugs to change our minds.