A joint effort to tackle obesity and diabetes

According to the Centers for Disease Control and Prevention (CDC), approximately 65 percent of adults in the United States are either obese or overweight, and therefore run the risk of suffering from chronic health conditions such as type 2 diabetes, cardiovascular disease and high blood pressure. This expanding epidemic appears to involve cultural, genetic and physiological factors that range from an overabundance of super-portioned junk food to how the brain regulates appetite. Researchers across the Yale campus are covering all the bases to uncover what causes obesity and how to counter its devastating effects.

A look at the culture surrounding food may go a long way toward explaining the rise of obesity, according to Kelly D. Brownell, Ph.D., professor of psychology and epidemiology. The fact that obesity has skyrocketed over the last 30 years in the U.S. and elsewhere in the developed world “just screams out environmental causes,” Brownell says. Unhealthy foods not only come in larger portions than ever before, but these foods are aggressively marketed and far cheaper and easier to obtain than healthier foods. “You put those factors together,” says Brownell, “and it’s hard to believe that we could have anything other than a bad diet.”

Named one of Time’s 100 Most Influential People last year, and cofounder and director of Yale’s Rudd Center for Food Policy and Obesity, Brownell is well poised to help change this picture. The Rudd Center deals in what he calls “strategic science,” in which research results are intended to help guide public policy. Brownell has helped build visibility of the center in the media, the food industry and the government by providing expertise for such initiatives as the recent move by New York City to ban trans fats and require calorie-labeling in restaurants. The range of topics covered by researchers at the center ranges from the social stigma of being overweight or obese to the possibility that food may be addictive in some people; in July, a Rudd Center conference brought together basic and clinical scientists with public policy experts and government officials to explore the idea of food addiction.

At the Rudd Center, established with a $7.5 million gift from California food and wine magnate Leslie Rudd, scientists are also targeting childhood obesity by focusing on food served in schools. In March, Brownell testified before Congress that schools provide an unsafe nutrition environment for children, citing the array of high-fat, high-calorie foods and beverages sold in schools. In Connecticut, research led by Marlene B. Schwartz, Ph.D., director of research and school programs at the Rudd Center, was a valuable resource for legislators regarding a bill that was enacted last July banning the sale of all beverages in schools except milk, water and pure fruit and vegetable juices.

But while the environment undoubtedly plays a major role in obesity, there are physiological factors that influence it as well. Research on adolescents led by Sonia Caprio, M.D., professor of pediatrics, has shown that the distribution of abdominal fat varies by ethnicity. African-Americans have less fat in and between internal organs than do Caucasians and Latinos, and they rarely develop fatty liver disease. Latinos, who have more visceral fat, tend to deposit fat in the liver, which can lead to inflammation and cirrhosis.

Caprio recently conducted a study that showed that the deposition of fat in muscle is also different among ethnic groups, and that it may relate to insulin resistance, in which the body’s cells become resistant to the effects of insulin. Insulin helps transport glucose into muscles and other tissues, and insulin resistance can lead to type 2 diabetes. Approximately 16 percent of children and adolescents are now overweight according to the CDC, putting them at risk for type 2 diabetes. Excess weight can also lead to impaired glucose tolerance (elevated blood glucose levels two hours after ingesting glucose), which can rapidly progress to diabetes in adolescents, so Caprio is also looking at how to treat this condition. She is heading research funded by the National Institutes of Health on the effectiveness of the drug rosiglitazone in correcting pre-diabetes. “Diabetes is coming on board at least two decades earlier than what we saw in the past,” says Caprio, who stresses the importance of addressing obesity in adolescents in order to prevent the disease.

While Caprio is working on the relation of muscle fat to insulin resistance, Gerald I. Shulman, M.D., Ph.D., professor of medicine and cellular and molecular physiology, and colleagues are examining fat on the cellular level. Their work has shown that intracellular fat that accumulates in liver and muscles can trigger insulin resistance. Obesity is one of the ways in which this type of fat builds up, and Shulman’s lab is now trying to figure out ways of melting it away. Along with Kitt F. Petersen M.D., he has shown that even modest weight reductions of 12 to 14 pounds will dissolve the intracellular pool of fat in the liver and reverse hyperglycemia.

“The answers to obesity are going to come from a fundamental understanding of the processes that determine why we eat and how we burn calories,” says Robert S. Sherwin, M.D., the C.N.H. Long Professor of Medicine. Insulin influences a sense of fullness, and Sherwin suspects that the brain, like other organs in the body, can become insulin-resistant. He is also studying how the brain senses glucose and how that process relates to eating and energy expenditure. He has shown that hypoglycemia causes rats to gain weight, not because they eat more, but because they appear to burn fewer calories.

Other researchers at the medical school are focusing on the brain’s role in energy expenditure and the behavioral aspects of eating. Studies in mice led by Tamas L. Horvath, D.V.M., Ph.D., chair and professor of comparative medicine and obstetrics, gynecology and reproductive sciences, and have neurobiology, have shown that estrogen regulates the brain’s energy metabolism in much the same way as leptin, another hormone that has attracted a great deal of attention because of its role in controlling appetite. Horvath is studying how higher brain regions, such as the hippocampus and cortex, help regulate food intake.

He’s also looking at the other side of the coin by trying to decipher how obesity may lead to metabolic changes that alter cortical function, which could have implications for neurodegenerative disorders such as Alzheimer’s disease.

Our bodies and brains evolved over millennia when food was scarce to become highly efficient at obtaining and absorbing nutrients, but in a modern environment in which it is increasingly easy and cheap for us to eat more than our fill, and harder to work it off in daily activities, it’s little wonder that obesity is a growing problem.

Fortunately, clinical investigations, psychological studies and basic biological research are all in place at Yale to attack obesity from every angle.

“On this issue you cannot have the typical ivory tower approach,” said Horvath. “You need to combine different views and see what comes out of that.”