As a nation, America is about 4 billion pounds overweight. This excess flab puts us at higher risk for a collection of medical complications, including high blood pressure, heart disease, and diabetes. Jeffrey Friedman has dedicated his career to unraveling the molecular mechanisms that regulate body weight. Using advanced techniques in neurobiology and genetics, Friedman has identified and characterized the activity of leptin, a hormone secreted by fat cells that balances food intake and energy expenditure. By studying leptin—and continuing to search for other genes that influence weight in humans—Friedman hopes to lay the foundation for developing therapies to combat obesity.
Friedman wasn't born with a burning passion to do science. As a young man, he aspired to becoming a physician. "Where I grew up, the highest form of human achievement was to become a doctor," he says. "And I didn't strongly object." So Friedman entered a six-year medical program out of high school and received his M.D. at the age of 22. But after a year-long fellowship working in the lab of Rockefeller's Mary Jane Kreek, he fell in love with the science life. "As a doctor, you're trained to absorb the facts you're given and accept them," says Friedman. "Science is almost the opposite. It's a frontier of discovery that's always moving. And I decided I wanted to do research."
When Friedman started his own lab at Rockefeller, he turned his attention to the question of weight regulation. Working with a special strain of obese mice, Friedman set out to identify the hormone that normal animals use to control their appetite—a molecule that was missing in the plump rodents. After eight long years—on May 8, 1994, at 5:30 a.m.—he found what he was looking for: evidence that he'd located the gene that produces the hormone he later dubbed leptin, after the Greek word for "thin." It was astonishingly beautiful, he says of the x-ray film that nailed the gene, a piece of data that now hangs on his office wall.
Leptin feeds into the circuit of neurons in the brain that controls eating and energy expenditure. When an animal loses weight, leptin concentrations fall. This dip in leptin levels instructs the body to search for food. In studies of obese mice, Friedman has found that leptin actually restructures the brain, rewiring the neural circuit that controls feeding. The hormone reinforces the nerve cells that encourage the body to slenderize and prunes the neurons that compel eating.
Since the early discoveries, Friedman and other scientists have found that a certain percentage of obese people have defects that render them leptin deficient. Restoring their leptin brings their weight back to normal. "I like the idea that some people have benefited from my work," he says. More recently, Friedman has taken the hunt for the genes that make us fat to Kosrae, a small island in the Pacific where obesity is rampant. By analyzing DNA collected from all the adults on the island, Friedman hopes to learn more about why some people are overweight while others are lean.