Gene Found That May Lead to Obesity
In a major step toward understanding and treating the weight problems that afflict nearly one-third of all Americans, researchers at Rockefeller University in New York announced Wednesday that they have identified and cloned a gene responsible for obesity.
Jeffrey Friedman, who led the research at the university’s Howard Hughes Medical Institute, said the group has cloned a gene responsible for obesity in mice and identified a human gene that is 85% identical to the mouse gene and is likely to play a similar role in regulating weight gain in humans.
These genes are called “obese” because they cause secretion of certain proteins or “satiety factors” in the fat tissue that Friedman believes enter the bloodstream and send a “stop eating” signal to the hypothalamus, the part of the brain that controls appetite. A single defect in the obese gene results in obesity because the gene fails to send or receive that signal, suggest Friedman and five associates in an article in today’s issue of the journal Nature.
“We feel this is a significant breakthrough in understanding the biology of obesity,” said Phillip Gorden, director of the National Institute of Diabetes, Digestive and Kidney Diseases. Gorden compared the satiety factor’s impact on weight regulation to insulin’s regulation of the level of sugar in the body.
One of three Americans is 20% or more above their ideal body weight, a condition defined as obesity and associated with diabetes, high blood pressure and certain cancers. During his news conference, Friedman said studies in twins have shown that about 80 percent of the propensity for obesity is genetically controlled.
Although the discovery should trigger a sharp increase in obesity research to study the significance of the satiety factor, Gorden said it is too early to tell whether it will directly lead to new drug treatments for obesity.
“The treatment of obesity still relies on diet and exercise. Those are still important,” said Gorden. “This is no magic bullet.”
Nevertheless, scientists say research into genetic causes of obesity will ultimately help provide a more balanced approach to treating obesity. “You have to attend to it as an organic problem, not a behavioral problem,” said Rudolph Leibel, a leading researcher in obesity research at Rockefeller University.
Friedman’s work builds on decades of research at the Jackson Laboratory in Bar Harbor, Me., that has identified five mutant genes associated with obesity in mice. In the early 1970s, Douglas Coleman, a senior researcher, clarified the roles of two of the genes by sewing together a mouse with the “ob” (obese) gene and another obese mouse with a related mutant gene called “db” so that the blood from each mouse would pass to the other.
The mouse with the db gene overproduced the satiety factor but kept eating because it didn’t have a receptor for the appetite suppressing message. The ob mouse, by contrast, had the receptor but was not producing enough of the satiety factor.
When the two mice were sewn together, the excess satiety factor from the mouse with the db gene passed through the blood to the mouse with the ob gene, sending a strong signal to stop eating. The ob mouse starved to death.
“Friedman’s work followed up nicely on this,” said Coleman, who is now retired. “All our predictions were true, but we weren’t in a position to isolate the satiety factor. It’s gratifying to see that happen now.”
Coleman’s work narrowed down the location of the ob gene to a single chromosome. Friedman’s group took chromosomes from the obese mice, cut them up into tiny pieces and used sophisticated techniques to home in on the ob gene, finally finding one gene that binds to fat tissue, where the satiety factor is produced. The gene sequence in the mouse gene was then used to locate a human gene with a similar sequence.
Friedman said he knew he had identified the right gene on May 8, when his research group discovered that of two strains of the same mutant gene, one produced a large amount of the messenger ribonucleic acid (RNA) while another created none. The results proved that the gene he isolated controlled the production of the RNA, the working blueprint for the satiety factor protein Friedman believes is responsible for regulating weight gain.
He was then able to reproduce, or clone, the isolated gene.
Friedman said his next task is to test the satiety factor in animals. He will also try to identify the receptor that receives the message and passes it on to the brain. Success in these tasks would help in the development of drugs accurately targeted to treat obesity.
Friedman said the gene he isolated may also shed light on a mysterious problem faced by the Pima tribe of Native Americans in Arizona. The tribe has an extremely high rate of obesity, and as many as half its members suffer from diabetes.
Scholars have suggested that these Indians, living in harsh desert conditions, acquired “thrifty” genes that helped them survive in times of famine by storing more fat from the same amount of food. With the prosperity and sedentary life that came with Western civilization, the “thrifty” genes became a liability, causing the storage of excessive amounts of fat.
Though Friedman’s discovery may be an important clue to unraveling the mystery of how obesity occurs, scientists agree that the causes of obesity are likely to prove complex and varied.
UCLA psychiatry professor Ernest Noble, for example, has conducted a study that suggests obese people may have what he calls the “sweet tooth” gene that gives them special pleasure from eating sugar.
Noble called these people “carboholics” and hypothesized that they compensate for shortfalls in other genes that offer pleasure by consuming large amounts of sugar that provide an alternative reward.
Teams of researchers on both coasts are already racing to develop drugs for obesity. A West Coast team is headed by Sequana, a San Diego company. The East Coast team is led by a Boston-based venture company, Millenium, and has Friedman as an adviser.
Friedman’s discovery seems likely to accelerate the effort. “Although multiple genes probably play a factor in obesity,” said Mark Levin, founder of Millenium, “influencing one might break the chain and have a big impact on the others.”
