Thursday, December 2, 2004
Webcast 10:00 a.m.-11:00 a.m. ET
Over the course of a year, a typical American consumes nearly a million calories and yet weight generally fluctuates very little. That's because the body has mechanisms for keeping track of calories and carefully balancing food intake and energy output. And that's what makes dieting so difficult. As we cut calories and lose weight, our metabolism slows, making it more difficult to take off the pounds. Obesity, then, is not the result of a complete lack of discipline but is largely a function of biology.
Studies of twins and adopted children show that obesity is heritable and that genes play an important role in determining body size. In the past decade, researchers have discovered some of these genes and are learning how they influence eating and body weight. Studying mice that are massively obese, Dr. Friedman and his colleagues identified the gene for leptin, a hormone produced by fat cells. Leptin-named after the Greek word for "thin"-feeds into the circuit of neurons in the brain that controls eating and energy expenditure. When we lose weight, leptin concentrations fall. This dip in leptin levels instructs the body to find more food. For this reason, most diets eventually fail.
Dr. Friedman introduces the genes and circuits that control appetite. By understanding how these systems interact with the environment, researchers might someday develop treatments for obesity.
Understanding Fat: Syndrome X and Beyond
Webcast 11:30 a.m.-12:30 p.m. ET
When it comes to weight control, appetite isn't everything. Our relative leanness-or lack thereof-also depends on how our bodies balance the storage and burning of dietary fat. And what we eat can make a big difference. Fat, it turns out, carries instructions about how it should be used. Saturated fats, the type found in meat and dairy products, are hard for cells to break down, so they tend to get tucked away. Unsaturated fats, found in olive oil and other plant oils, are readily consumed for energy. What's more, they direct the body to burn more fat.
Having too much fat lying around is bad because it can trigger insulin resistancethe first step on the path to diabetes. Fat encourages muscle to reject glucose as an energy source. To keep this sugar from building up in the blood, the pancreas produces extra insulin. Over time, however, the pancreas becomes overworked and can no longer compensate. So blood sugar rises and diabetes develops.
Exercise improves the situation, because the stretching of muscle fibers provokes cells to take up glucose, removing it from the blood. Unfortunately, more weight usually goes hand in hand with less exercise-even in mice. Rodents treated to a "Western" diet, rich in fat, grow pudgy and sluggish, sitting more often than they scurry. In humans, a high-fat diet coupled with poor exercise leads to syndrome X, a metabolic disorder characterized by insulin resistance, high blood pressure, and heart disease.
Dr. Evans describes how fat communicates with muscle and how diet and exercise influence that relationship, promoting good health or precipitating disease.
Friday, December 3, 2004
Balancing the Fat Equation
Webcast 10:00 a.m.-11:00 a.m. ET
Like most things in the body, metabolism is governed by a complex interaction among genes. In particular, a family of proteins called PPARs (for peroxisome proliferator-activator receptors) controls how the body uses sugar and fat. One member of this family, PPAR-gamma, acts as a master switch that drives the formation of fat cells and regulates the storage of fat. The receptor snatches fat from the blood and squirrels it away inside fat cells. By whisking fat from the blood, PPAR-gamma encourages muscle to burn sugar and allows the body to remain sensitive to insulin. Drugs that activate PPAR-gamma are currently used to treat diabetes. Although they don't help people lose weight, the drugs do restore patients' sensitivity to insulin.
A sister protein, called PPAR-delta, regulates how muscles burn fat. When kept on a high-fat diet, mice that lack PPAR-delta become obese. Mice that are engineered to produce an overactive version of the receptor in their muscle tissue remain sleek and lean. PPAR-delta revs up cellular fat-burning pathways and beefs up the animals' slow-twitch muscle mass. This type of muscle, highly developed in marathon runners and migrating birds, prefers to use fat as an energy source. The engineered animals put this muscle to good use. When placed on a rodent-sized treadmill, these "marathon mice" will run twice as far as their normal relatives.
Dr. Evans reviews how PPARs regulate body weight-and how drugs that stimulate PPARs might help people slim down and improve their health without altering their appetite.
Exploring Obesity: From the Depths of the Brain to the Far Pacific
Webcast 11:30 a.m.-12:30 p.m. ET
By four years old, the boy weighed 90 pounds and consumed more than 1,100 calories in a single sitting-approximately half the recommended daily intake for an adult. Genetic testing revealed that the child possessed a rare mutation that disabled his leptin gene. Without the hormone, he kept gaining weight because his body told his brain that he was starving. When doctors treated the boy with leptin, his calorie intake was slashed by 84 percent and he eventually got down to a normal weight for his age.
In studies of obese mice, Dr. 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.
Leptin isn't the whole story. For most of us, a combination of genes regulates our weight. These powerful systems are part of our genetic heritage. Some researchers think that such "thrifty genes" provided our ancestors with a survival strategy for coping with famine. Individuals who stored calories in times of plenty could avoid starvation when food grew scarce. Thus, obesity could be a product of these genes that evolved to keep us alive.
Dr. Friedman describes his continuing hunt for the genes that make us fat, research that has carried him to a small island in the Pacific where obesity is rampant. By analyzing DNA collected from all the adults on the island, Dr. Friedman hopes to learn more about why some people are overweight while others are lean.
© 2013 Howard Hughes Medical Institute. A philanthropy serving society through biomedical research and science education.