Rockefeller University's Jeffrey M. Friedman, M.D., Ph.D., a molecular geneticist whose discovery of the hormone leptin and its role in regulating body weight has changed our understanding of the causes of human obesity, has received two prestigious awards for this work: the Gairdner Foundation International Award and the Passano Foundation Award.
Prior to his groundbreaking research, little was known about the components of the biologic system that controls weight, with many scientists questioning the very existence of such a homeostatic system. With leptin and Friedman's subsequent studies, the logic of an entirely new physiologic system has been established with direct implications for the pathophysiology of human obesity.
Friedman, Marilyn M. Simpson Professor and head of the Laboratory of Molecular Genetics at Rockefeller and an investigator at the Howard Hughes Medical Institute, received the Gairdner Award and gave a talk on the genetic roots of obesity on Tues., April 5 in Toronto, Canada. On Tues., April 19, he will receive the Passano Award at the Center Club in Baltimore, Md., and give the Passsano Foundation Award lecture at Johns Hopkins University School of Medicine.
Discovery of leptin and its role in regulating body weight
In December 1994, Friedman and his colleagues published a landmark paper in the journal Nature, in which they identified a gene in mice and humans called obese (ob) that codes for a hormone he later named leptin, after the Greek word leptos, for thin. Friedman and colleagues showed that leptin is a hormonal signal made by the body's fat cells that regulates food intake and energy expenditure. Leptin has powerful effects on reproduction, metabolism, other endocrine systems and even immune function.
Mice that lack ob, and thus do not produce leptin, are massively obese, weighing as much as three times as their normal littermates. Friedman showed that after normal and ob mice are injected with synthetic leptin, they are more active and lose weight. In addition, humans lacking leptin eat copious amounts and are massively obese. Leptin treatment of these individuals leads to massive weight loss. The dramatic effect of leptin in these patients establishes a key role for this hormone in human physiology.
However, the majority of obese have very high levels of leptin circulating in their blood. Friedman's lab went on to show that high leptin levels are associated with resistance to leptin and provided evidence that suggests that animals destined to be obese increase their production of leptin to satisfy a higher set point for weight. These observations have reframed views on the pathogenesis of obesity and suggested that the development of approaches to improve leptin response in resistant individuals could provide new treatments for obesity.
Leptin itself has proven to be an effective therapy for a number of other human conditions associated with low leptin levels, including several different forms of human diabetes and a condition known as hypothalamic amennorhea. This condition, which develops in extremely thin women -- often ballet dancers or long-distance runners -- is one of the most common causes of infertility in women, and leptin treatment restored reproductive function in these patients. In addition, a subset of obese individuals also has relatively low leptin levels, and it appears that these individuals lose weight with leptin treatment. Friedman is now performing clinical studies at The Rockefeller University Hospital to determine the effects of leptin on the response to significant weight loss in obese patients on a very low calorie diet.
In 2002, Friedman and colleagues at Rockefeller and the University of Wisconsin at Madison uncovered another component of the biological system that controls body weight: they showed that an enzyme called SCD-1 works through leptin to signal the body to either store fat or burn it. The scientists believe that leptin acts in part by suppressing SCD-1's activity, which in turn activates a metabolic pathway that promotes the burning of fat.
Last year, Friedman and colleagues at Rockefeller and Yale showed that leptin affects both the architecture and function of neural circuits in the brain by changing the wiring of the brain, a phenomenon known as plasticity. Leptin alters the wiring by controlling synapses -- the inputs and outputs to neurons that, in this case, regulate feeding behavior.
Syndrome X studies on the island of Kosrae
Friedman also is the director of the Starr Center for Human Genetics, one of the largest U.S. centers for the study of diseases linked to heredity. Friedman, with Jan Breslow, M.D., Frederick Henry Leonhardt Professor and head of the Laboratory of Biochemical Genetics and Metabolism, and Markus Stoffel, M.D., Ph.D., Robert and Harriet Heilbrunn Professor and head of the Laboratory of Metabolic Diseases, leads a team of Rockefeller researchers that is studying the genetic causes of a cluster of health problems called Syndrome X -- obesity, diabetes, high blood pressure and high blood cholesterol -- in a remote population of over 3,000 people on the Micronesian island Kosrae.
The Rockefeller scientists have turned to the people of Kosrae for two reasons. One, most Kosraeans can trace their heritage to a relatively small "founder " population of about 50 people who came from Polynesia about 1,000 years ago. Later, in the mid- to late-19th century, Caucasian whalers visited and in many cases settled on the island, and so today many Kosraeans can trace their ancestry to both groups.
The second reason the Kosraeans are ideal for studies of Syndrome X involves the more recent "westernization" of their lifestyles. For most of their thousand-year history, Kosraeans were active. They ate native foods and were reported to be relatively lean. But in the years following World War II, most began leading a sedentary lifestyle while eating foods with high salt and fat contents. Subsequently, a disproportionate percentage of people on the island have developed one or more conditions associated with Syndrome X.
By analyzing the genetic inheritance patterns of the entire Kosraean population, Friedman, Breslow and Stoffel hope to solve the ongoing mystery of why some people develop these diseases, while others with the same lifestyle do not.
War on obesity, not the obese
Friedman recently has become concerned about the stigmatization of the obese.
In a "Viewpoint" article in the journal Science last year and another article in Nature Medicine, Friedman argued that obesity cannot be ascribed to a breakdown in willpower. Genes modified by environmental factors, he explains, play important roles in determining a person's body weight. The Science article was subsequently chosen for publication in the anthology of the Best American Science and Nature Writing 2004 published by Houghton Mifflin. In this article Friedman wrote, "While answers are beginning to emerge as to why so many of us are obese, there can be no meaningful discussion on this subject until we resist the impulse to assign blame. Nor can we hold to the simple belief that with willpower alone, one can consciously resist the allure of food and precisely control one's weight."
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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