The Albert and Mary Lasker Foundation announced today that Howard Hughes Medical Institute (HHMI) investigator Jeffrey M. Friedman of Rockefeller University and Douglas Coleman of The Jackson Laboratory will share the 2010 Albert Lasker Basic Medical Research Award.
Friedman and Coleman are being honored for discoveries that led to the identification of leptin, a hormone that regulates appetite and body weight. Their findings have helped demonstrate that obesity can be a result of metabolic and hormonal disruptions rather than lack of willpower, and have opened obesity research to molecular exploration. The awards will be presented at a ceremony on October 1 in New York City.
Including Friedman, 11 current HHMI investigators have won Lasker Awards, the nation's most distinguished honor for outstanding contributions to basic and clinical medical research. Since 1945, the Lasker Awards program has recognized the contributions of scientists, physicians, and public servants around the world who have made major advances in the understanding, diagnosis, treatment, cure, and prevention of human disease. Seventy-nine Lasker laureates have gone on to receive a Nobel Prize.
Friedman has dedicated his career to unraveling the molecular mechanisms that regulate body weight. When he started his lab at Rockefeller, he began working with two strains of obese mice that Coleman had used in his own research decades earlier. Coleman's studies demonstrated that normal mice are able to maintain a healthy weight in part because they make a “satiety factor,” a substance that restrains appetite. The obese mice do not make that appetite-suppressing substance on their own, but if they are exposed to it via the blood of another animal – even a different strain of obese mice called diabetes mice – they stop eating.
Friedman searched for the defective genes in two strains of mice – obese and diabetes mice – with the aim of isolating an appetite-suppressing hormone and its receptor. After seven years, in 1994, 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 leptós, which means "thin." When Friedman gave the obese mice leptin supplements, the animals lost weight, became more active, and began responding to insulin.
In 1995, Friedman, as well as another research group led by Louis Tartaglia at Millennium Pharmaceutical Inc., showed that the gene that is defective in diabetes mice encodes a receptor for the leptin hormone. As Coleman’s work had hypothesized earlier, these mice overeat due to an inability to respond to the appetite-suppressing substance in their blood.
Leptin regulates the activity of a 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. At first, leptin seemed to be simply a signal sent by fat cells to the brain: "We're full. Stop eating." But as leptin research took off, the picture has become more complicated.
Friedman has found that leptin can actually refine the structure of neurons in 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. Scientists have found large numbers of leptin receptors on the hypothalamus, a brain structure known to control appetite. Many other effects of leptin—or the absence of leptin—seem to work through the blood.
Since the early discoveries, other investigators have identified a small number of obese people who have genetic defects that render them leptin deficient. Restoring their leptin brings their weight back to normal. Most obese individuals, however, possess large amounts of circulating leptin, yet remain overweight, and Friedman has shown that high levels of leptin can lead to leptin resistance.
Scientists have also discovered that inadequate leptin underlies other pathologies, including lipodystrophy, in which patients lack sufficient fat tissue and underproduce leptin, causing insulin resistance and high cholesterol. Preliminary studies suggest that leptin therapy can provide therapeutic benefits for these individuals.
More recently, Friedman has taken the hunt for the genes that regulate weight 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.