Among the naturally mutant mice collected over the years at the Jackson Laboratory was a small animal with a brilliant yellow coat known as Ay, or yellow agouti, which had originally been bred in China for mouse fanciers. It turned out to be one of five mutant strains of mice that were obese because of a single gene mutation. In addition to Ay, the other mutant strains were obese (ob), diabetes (db), fat, and tubby, and they proved essential to genetic studies on metabolism and weight maintenance.
"There had been abundant evidence for decades that there was a potent biological system that regulates weight," explains Jeffrey Friedman, a Hughes researcher at The Rockefeller University in New York. During the 1950s and 1960s, all attempts to tease out the mechanics of that system by biochemical means failed, but by the 1980s it became possible to plot an alternative approach using genetics. "By identifying individuals, either human or animal, with a predisposition to disease," says Friedman, "one could go on to identify the gene."
Friedman decided to tackle the issue of obesity around 1986, and the individuals he chose to study were, of course, of the furry, scurrying sort. Both the ob (or obese) and the db (or diabetes) mice typically weigh three times what a normal mouse weighs and accumulate five times the normal amount of body fat. During nearly eight years of complicated genetic experimentation, Friedman and his colleagues provided the first glimpse of the biological system that controls the intake of food and the metabolism of fat and showed that the ob and db mice reflect two aspects of the same biological system.
The researchers discovered that ob mice become fat because they lack a single gene, ob. This gene, normally active in fat cells, produces a protein that travels through the bloodstream to the brain and tells it, in effect, "I'm full." Friedman named the missing gene's product leptin, after the Greek word for thin (leptos). It then turned out that db mice lack a gene containing the instructions for making the leptin receptorthe biochemical antenna that receives the leptin signal from the fat cells. In other words, the brain of db mice is unable to receive the message "I'm full" dispatched by the fat cells.
Finding these mouse genes enabled researchers to discover the same genes in humans. The initial report on the obese gene, which appeared on the cover of the journal Nature in December 1994, is framed and displayed prominently on Friedman's office wall (with one unusual annotation: a longtime hockey buff, Friedman asked all-star forward Mark Messier to autograph the journal just beneath a picture showing an obese mouse outweighing two normal mice).
Although the biology of the system is extremely complex and still being worked out, leptin appears to play a critical role in day-to-day biology. "If the fat mass falls," Friedman says, "the level of leptin falls, and the urge to eat goes up. After an eating binge, the level of leptin rises, which is a signal to eat less. In addition to modulating food intake and energy expenditure, leptin has an effect on fertility, temperature maintenance, and fat and glucose metabolism." It has become clear, in other words, that leptin sits at the junction of many primal human activitieseating, procreation, basic health, basic activity.
Not surprisingly, leptin appears linked to human disease. Several childhood diseases of obesity have been associated with mutations in leptin genes. Two children in England, for example, experienced horrendous obesity disordersa two-year-old weighed in excess of 64 pounds and an eight-year-old weighed in excess of 189 pounds. "Both have been treated with leptin," Friedman says, "and both have responded very well."
The leptin story carries within it a seed of caution. Initial press reports about the gene's discovery in 1994 emphasized potential applications for human weight controlan emphasis that the marketplace was quick to embrace. Amgen, a prominent biotechnology company based in Thousand Oaks, California, invested tens of millions dollars to develop leptin as a human therapeutic drug.
In human trials to date, however, the results have been variable: some obese people lost up to 15.6 pounds after six months of treatment, while others did not respond to leptin at all. Friedman points out that many obese people already have high levels of leptin in their blood, which implies they are less sensitive to the hormone than lean people. The reasons for this difference are still obscure. But obesity does sit at the nexus of many basic areas of biology, and tubby mice may yet have a lot to say to the couch potatoes, foodaholics, and compulsive snacksters among us. Friedman's group is currently tracing the influence of leptin as it moves through the brain.
Stephen S. Hall
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Carrying five times as much fat as its normal sister, this obese mouse lacks a single gene: ob.
Jeffrey Friedman, who discovered the gene that encodes leptin, is trying to trace its effects.
Photos: Kay Chernush