Hormone Found to Cause Weight Loss in Obese Mice : Health: Researchers identify a similar fast-acting substance in humans. They say reducing drug may result.

Perhaps heralding a leaner future for an ever-fatter America, scientists have gotten genetically obese mice to lose a third of their weight in two weeks by injecting them with a newly discovered hormone that regulates body fat.

Besides studying the grotesquely obese mice, the scientists, led by Jeffrey M. Friedman, a molecular geneticist at the Howard Hughes Medical Institute and the Rockefeller University, have found a nearly identical hormone in human beings.

Moreover, while the thrust of the work involved the mouse hormone, the researchers also found that obese mice injected with the human hormone similarly lost weight. This suggests that the hormone might someday be used as a high-tech reducing drug in people.

Claiming the pioneer’s right to name the discovery, Friedman proposes calling the hormone “leptin,” from the Greek for “thin.”

“The fact that human leptin reduces weight in the mice raises the possibility that giving leptin to people might have similar effects,” Friedman said.

“Extremely exciting,” said Dr. Carl Grunfeld, an endocrinologist at UC San Francisco and the Veterans Affairs Medical Center. “This is perhaps the major finding in the field of obesity in the last two decades.”

“A wonderful advance,” said Dr. Susan Yanovski, executive secretary of the National Task Force on the Prevention and Treatment of Obesity. “But we’re a long way from knowing what’s going on in human beings with obesity, or the best way to treat it.”

In the recent studies, Friedman and co-workers showed that 10 obese mice injected with leptin lost an average 30% of body weight after two weeks. After 33 days, the mice had lost an average of 40%. A group of control mice, injected with saline, exhibited no such weight loss.

Stephen K. Burley, a biochemist also at Howard Hughes Medical Institute and Rockefeller University, said, “It was sort of hard to believe it when the mice started to drop weight. It was amazing.”

Burley added, “The effect on these mice was like the before and after shots in those improbable body-building advertisements.”

The federal government estimates that 58 million adults, or a third of the adult population, are obese, which is defined as weighing 20% or more above the ideal weight. That’s a substantial jump from a decade ago, when a quarter of American adults were obese, according to the National Institute of Diabetes, Digestive and Kidney Diseases.

The Howard Hughes-Rockefeller study is one of three groundbreaking papers on leptin to appear in the latest issue of the journal Science. The other papers are by scientists at Amgen, the Thousand Oaks bio-tech firm, and at Hoffman LaRoche Inc., the drug company.

The Science issue was scheduled to be released Friday, but that embargo was broken Wednesday when Lehman Bros., the investment bank, touted the studies in a stock report highlighting Amgen. After heavy trading Wednesday, Amgen stock rose 4 3/8, to 84 1/4.

In March, Amgen paid Rockefeller University $20 million for exclusive rights to develop and market products based on the so-called obesity gene. Additional royalties will flow to the university if Amgen markets a drug.

Gordon Binder, Amgen’s chairman and CEO, said in a press conference Wednesday that “if things continue to go smoothly” the firm “would expect to start human testing next year.”

The search for this elusive substance began in the early 1970s, when Douglas Coleman, a senior researcher at the Jackson Laboratory in Bar Harbor, Me., showed that special, lab-bred obese mice, called ob/ob, appeared to lack something that controls appetite and body fat in other mice.

Last December, after eight years of experiments, Friedman and co-workers announced to great fanfare that they had identified a mutant gene in the obese mice that, they believed, made the creatures pile on fat.

Once the researchers knew the chemical code inscribed in that gene’s DNA, they used standard recombinant DNA techniques to insert a normal version of the gene into bacteria in test tubes. The bacteria then manufactured the gene product--leptin.

Not only did the leptin-treated obese mice trim down, the researchers reported, but other measures of metabolism also changed. Body temperature rose, appetite fell and the animals became more active.

The range of leptin’s metabolic effects indicates that it plays a central role in both monitoring and controlling body fat and energy balance, researchers said.

Friedman said that, in mice anyway, leptin appears to be secreted almost exclusively by fat cells. And the more fat on board, the more leptin in the bloodstream.

When leptin reaches a certain level, scientists believe, it signals those brain centers that control hunger and appetite, such as the hypothalamus, which is sometimes described as the body’s thermostat. In people with a normal leptin-producing gene, the brain then responds to the signal by regulating the body’s fat stores and energy balance.

In those with a defective gene, however, that feedback process does not work properly.

The obese mice offer graphic evidence for leptin’s vital feedback role. “Ironically, here’s a massively obese animal that thinks it’s starving because the signal’s been interrupted,” Friedman explained.

News of a substance that so dramatically alters body fat without known adverse effects had many people wondering if science hadn’t finally invented the proverbial free lunch. Or, failing that, at least a drug that might someday let people have their cake and eat it too.

“Oh no,” said Burley. “You wouldn’t even want the cake” if such a drug existed and you took it. “The mice treated with the hormone voluntarily eat less.”

Explaining that the treated mice also became more active, he added, “You would probably want to go run around or something.”

Another “cool” observation, Friedman said, was that normal mice injected with leptin lost some fat--but no muscle.

Although Friedman and co-workers found a leptin-like protein in several lean human beings they tested, they are not yet certain the hormone plays a role in human obesity.

But they did find that human leptin appears to affect the obese mice as profoundly as mouse leptin did, suggesting that the two species may indeed have a great deal of fat metabolism in common.

At the same time, there are animals, and perhaps people, that don’t react to leptin. Another type of genetically obese mouse, called db/db because of its profound diabetes, showed little or no response to leptin injections, according to studies by Friedman as well as by the researchers at Amgen and Roche.

To some scientists, that finding underscored the need to remain cautious about leptin’s future as a drug.

“If leptin plays a role in humans, it’s likely to be in the morbidly obese, and not all of them,” said Dr. C. Wayne Callaway, an endocrinologist specializing in obesity at George Washington University.

An important social implication of the obesity gene research, researchers say, is that it shows that obesity is not a weakness or a failure of willpower. In that sense, this high-tech lab work may help erase some of the stigma of being fat.