Why Eating Is so Natural
Last month, the Journal of the American Medical Assn. reported that leptin, a hormone discovered five years ago by Rockefeller University researcher Jeffrey M. Friedman, is not the weight-loss panacea once hoped. Some will no doubt regard this finding as yet another disappointing setback in the effort to make sense of the obesity epidemic. But the announcement might more accurately be seen as evidence of how far we have come in understanding what was a totally baffling conundrum: why so many have lost the battle to achieve and maintain a healthy weight.
Like all good science, the study of the genetics of obesity has proceeded in fits and starts, with success building on a foundation of failure. That leptin is not an easy cure for corpulence may have dashed unrealistic dreams of a magic bullet, but the identification of leptin and the gene that regulates it have lead to a radical new understanding of weight control.
The discovery of leptin offered the first tangible evidence of a theory, long held by Friedman and a handful of other researchers, that the regulation of eating behavior is, at its heart, genetic, that people act on biologically wired drives and that the intensity and duration of these drives vary with individual brain chemistry. This finding represents a remarkable breakthrough in the understanding of human disease and bolsters a controversial theory of human psychology. It offers irrefutable support for evolutionary biologist Edward O. Wilson’s once radical theory that genes can act directly to mold behavior; in this case, the highly complex and culturally laden behavior of eating. It is also evidence that this complex behavior can be modified and controlled through manipulation of an intricate pathway in the brain. With hundreds of researchers around the world exploring the molecular pathway the discovery of leptin blazed, it is only a matter of time--and perhaps not much time--before a true understanding of what underlies the nation’s growing collective girth emerges.
While the laws of physics dictate that fat people eat more and/or exercise less than do thin people, the laws of genetics determine who among us will be driven to eat too much. This is not to suggest that genetics is destiny: We all know people who have the vigilance to overcome their biology. But for a burgeoning number of us, the tug of genetics has become irresistible. This is why most weight-loss programs fail, even for people whose very lives depend on them. It is why obesity-linked gall bladder disease, cardiovascular disease, hypertension and cancer are skyrocketing. One in two Americans are overweight, and nearly one in five is obese: more than 30% are above their ideal body weight. Nineteen million Americans, including 20% over age 60, have obesity-linked diabetes. But even these statistics can’t begin to describe the damage that being overweight wreaks on our media-driven self-esteem. It is sobering to consider that “Baywatch,” which portrays a world in which being slim is not optional, is the most popular television series on the planet.
What is known is that obesity is one among a group of particularly intractable disorders, including heart disease, diabetes and hypertension, that arise not from purely genetic causes, or from environmental influences, but from a complex interaction of both. Most modern-day scourges for which there are no good treatments are the consequence of this interaction. Attempts to control and curb the environmental influences on obesity have largely failed because they underrate the power of human nature: McDonald’s McLean lasted only long enough to whet appetites for Burger King’s Triple Whopper.
The discovery of leptin allowed scientists to see for the first time the underlying forces driving this hunger--that is, why so many of us eat more than is good for us. It was the defining event that transformed obesity research from a largely third-rate, speculative backwater to a viable scientific inquiry. The once-popular notion that common obesity was the result of some “glandular irregularity” or gross metabolic defect was largely laid to rest, as were psychological theories that blamed excess pounds on gluttony or a weakness of will. It became clear why generation after generation of diet drugs, some of them dangerous, had in the long run proved ineffective, and why so few are able to stick to the sensible, low-calorie diet regimens prescribed by talk-show hosts, glossy magazines and well-meaning friends. It has become clear to even the most skeptical of scientists that the key to effective weight control is genetic understanding.
After the publication of Friedman’s discovery in a cover story in the journal Nature, hundreds of millions of dollars poured in to support research into the genetics of weight regulation. More than 800 papers on leptin were published in three years, research that lead scientists to conclude that the hormone is at the hub of a labyrinthine system that precisely regulates body weight. Through this work, scientists have gained critical insight into the workings of the brain’s weight-control center, an area of the hypothalamus that mediates between input from the environment and behavior.
Obesity expert Jeffrey S. Flier, professor and vice chair for research at the Harvard Medical School, has said that common weight problems will likely be traced to the brain’s inability to pick up or decipher hormonal signals produced by the leptin system, an elaborate chemical pathway that scientists are now scrambling to decode. He sensibly points out that the leptin system evolved to keep humans from starving, not to keep them slim. His research has linked leptin with fertility: In the absence of leptin produced by fat cells, animals (and humans) do not mature sexually and cannot reproduce. In part because of the impact of starvation on fertility, an innate biological response to limit weight gain was probably selected against by evolution, and most are biologically poised to reverse any slippage in body weight. This is why all but a few have such difficulty achieving and maintaining weight loss.
Humans can and do develop resistance to the leptin signal. This is certainly true for the obese. The blood of most severely overweight people is virtually swamped with the stuff. So it is not in the least surprising, as last week’s study concludes, that most obese do not lose weight when injected with still more of the hormone. But once the mechanism for leptin resistance is unlocked--as it almost certainly will be within the next half decade--new therapies for the disorder are sure to follow. What scientists are after now is a treatment that will work on a molecular level to tip the scales in the direction of a healthier body weight. Leptin per se is not that treatment, but there is no question that its discovery has brought us closer to finding one, and will one day be hailed as one of the most important biomedical findings of the 20th century.
