Weight-Loss Nirvana A
Substance That Makes Fat Mice Thin Just Might Work for Humans Too
In the US, where one in three adults is seriously overweight, the news
carried by the journal Science last week -- that Friedman and his colleagues at
the Howard Hughes Medical Institute and New York City’s Rockefeller University
had discovered a magical dose that melts fat in a matter of weeks -- resonated
with unusual force. Momentarily, at least, it encouraged the spirits of millions
of lifelong dieters and boosted the stock of Amgen, the biotechnical firm based
in California that holds the license on the underlying technology. It is too
early to predict, however, whether this rare elixir (called leptin, after the
Greek leptos, meaning slender) will be a stunning pharmaceutical (制药上的) success
or just another "miracle" cure that never pans out. Even if all goes well, it
could be five to ten years before leptin is approved in the US for human use.
Researchers must first demonstrate that leptin benefits people as well as
animals and that it causes no serious side effects. The search
for leptin began in the 1960s, when Douglas Coleman, a researcher at the Jackson
Laboratory in Bar Harbor, Maine, began studying a strain of fat laboratory mice.
In a series of creative experiments, Coleman surgically joined the blood vessels
of an .obese (肥胖的) mouse to those of a normal-size mouse, creating a sort of
artificial Siamese twin. What happened then was astonishing: the fat animal
immediately began to lose weight. This suggested that the blood of non-obese
mice carried an effective biochemical messenger, one that played an important
role in regulating appetite and metabolism (新陈代谢). But the mysterious agent was
present in such minuscule quantities that no one was able to isolate
it. Friedman picked up the challenge, applying new tools
developed by the field of molecular genetics. The secret factor, he reasoned,
must be produced by a gene that was defective in the obese mice. So he began to
hunt for such a gene, the ob, or obese, gene. Sure enough, late last year, after
eight years of effort, Friedman and his colleagues pinpointed the ob gene in
both average-weight and obese mice. They then inserted the normal gene into
bacterial (细菌的) cells, providing at long last detectable quantities of the
protein they called leptin. By injecting leptin into obese mice,
three separate teams of researchers, including Friedman’s, have confirmed that
this protein is indeed the blood factor that makes fat mice thin. But they are
still trying to puzzle out just how it works. Friedman, for one, believes leptin
is almost certainly a hormone that travels through the bloodstream to act on the
brain. In fact, it appears leptin may act in a feedback loop (反控循环) like the
temperature sensor in a thermostat (恒温器)--or in this case a "fatstat" -- to tell
the body whether to turn metabolism and appetite up or down. Thus when leptin is
low, hunger pangs increase, body temperature drops, and metabolism slows; when
leptin is high, everything reverses. In such fashion, the brain strives to
keep body weight stable and fluctuations small. Because leptin
is produced in fat tissue (组织), the fatter an animal is, the more leptin its
cells should make. Normal mice then respond to weight gain by turning out more
leptin. As a result, their appetites slow down and their energy consumption
speeds up. But the obese mice cannot produce leptin, so their brains never
receive this vital message. "These animals," says Friedman, "get fat because
they think they’re starving, and then when we give them the protein, they get
thin because they think they’re fat!" What, if anything, does
this have to do with people Perhaps a good deal. For humans have an ob gene
that is virtually the same as the mouse gene, and it is possible that at least
some folks have trouble keeping off kilos because of mutation (突变) in this gene.
Most experts, however, agree that defects in the ob gene are not likely to be a
major reason for obesity in people. But that does not mean leptin might not be
therapeutically (治疗学的) useful for many other overweight people. In last week’s
Science, for example, a team of researchers from the pharmaceutical company
Hoffmann-LaRoche described how they fattened lean mice by giving them
unrestricted access to high-fat food. Then they administered leptin. The mice
responded by cutting their food intake and shedding the extra grams, suggesting
leptin may have value in reversing more typical cases of weight gain.
What about side effects Injections of leptin do not, as one might fear,
turn lean mice into starving wretches. After losing weight, researchers from
Amgen reported, normal mice stabilize both their food intake and their
metabolism. Obese mice likewise reach an ideal leanness, and then stop losing
weight. The pattern of weight loss is also encouraging. For unlike extreme
calorie restriction, which can weaken muscle, leptin appears to melt fat while
leaving lean tissue untouched. On the basis of such data, Amgen (which paid
Rockefeller University $ 20 million for patent rights to make products based on
the ob gene) has announced that it hopes to begin making human trials as early
as next year. Many experts find these plans too optimistic. Just because
researchers have not noted worrisome side effects yet, critics say, does not
mean that none will emerge. Leptin, they point out, is a serious drug, not the
easy-to-swallow "thin pill" dieters have dreamed of for so long. To do its work,
leptin would probably have to be either injected daily or implanted under the
skin for life. In the laboratory experiments reported last week, the obese mice
started regaining weight as soon as the injections stopped. Even with a boost
from something like leptin, cautions Dr. Ahmed Kissebah, an obesity expert at
the Medical College of Wisconsin, the formerly fat cannot afford to become less
alert. "People will still have to lose weight the hard way," he predicts. "It’ll
be like diabetes: you still have to exercise and watch your food
intake." Regardless of what eventually happens in the
marketplace, the discovery of leptin is occasion for celebration. It has
provided scientists with a new way for exploring a still poorly understood
metabolic pathway, one that probably consists of many other equally powerful
compounds, each of which could lead to new drugs. To the millions of seriously
overweight Americans, help with a frustrating condition -- years of guilty
eating and self-recrimination -- may finally be on the way. The ob gene causes the fat cells to produce the hormone leptin. The fatter, the more hormones are produced.