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The best weighed plans of mice and men might hinge on a gene that determines the level we reach on scales and the size of our waistlines.
That was the message delivered by Dr. Jeffrey Friedman, to those attending the final session of IUSM Mini Medical School last semester.
Friedman, whose research of molecular mechanisms regulating food intake and body weight has been in the scientific spotlight in recent years, was the recipient of the medical school’s prestigious Steven C. Beering Award for the Advancement of Biomedical Science.
"Generally, there are two views about the nature of weight," said Friedman. "One view holds that we do have conscious control of weight, determined by how much food we consume and how much energy we expend. Certainly, environment and lifestyle are factors to be considered. The second view is that body weight is regulated by physiological factors over which we have little or no control."
As director of the Starr Center for Human Genetics and a professor at the Rockefeller University in New York City, Friedman headed a team credited with identifying a fat gene that could explain why some people are corpulent and others svelte. Their discovery followed up on research at a Bar Harbor, Maine, laboratory, where the blood vessels of an obese mouse were surgically connected to a normal-size counterpart, resulting in a dramatic weight loss for the larger rodent.
That finding caused him to pursue experiments to identify the defective gene that is the cause of the mouse’s obesity. After eight years of intensive investigations, Friedman and his colleagues isolated what they would identify as ob (obese) gene. They inserted a normal mouse gene into bacterial cells and it produced a protein called leptin.
"Basically, the ob gene is nature’s way of controlling weight," said Friedman, who also is an investigator at Howard Hughes Medical Institute. The ob gene in mice is virtually identical to the one found in humans. The ups-and-downs of weight regulation might quite literally be in a person’s head. Leptin created by the ob gene enters the bloodstream and travels to the hypothalamus, a portion of the brain that regulates various body functions. If a large volume of leptin is produced, the hypothalamus reacts by reducing appetite and accelerating the body’s metabolism. But if the ob gene is defective, it could reduce the amount of leptin produced, causing the hypothalamus to send a continuous message that the body needs to consume more food, resulting in a buildup of excessive fat and weight.
"The mice get fat because they think they are starving, but when we introduce leptin, they think they’re fat and stop eating," said Friedman. "It’s all a tricky delicate balance."
Friedman’s group reported two crucial experiments confirming ob’s signaling role: the ob protein must be shown to circulate in the blood, and injections of a normal version of the ob protein must reduce the weight of animals with mutations in their ob genes. Such experiments are now under way in Friedman’s lab.
All of this could mean good news to more than 60 million U.S. adults who are said to be obese, medically defined as being 20 percent or more above the ideal weight for a person’s height. For many, the extra pounds bring with them the added baggage of heart disease, diabetes, high blood pressure and other life-threatening maladies. More than 300,000 die each year because of obesity-related diseases.
Additionally, it’s estimated that $100 billion is spent annually in the United States for clinical treatments and diet fads to fight fat. Leptin clinical trials in humans are now underway.
