Inside Duke Medicine

Winning the obesity battle

Eat less and move more.

The secret to losing weight comes down to this rather simple prescription.

However, for the one-third of Americans considered obese, defined as having a body mass index, or BMI, of 30 or higher, losing weight is not a simple endeavor.

And surprisingly, scientists have few answers as to why certain people lose or gain weight while others do not or why certain obese individuals go on to develop life-threatening conditions, such as cardiovascular disease and type II diabetes. A lot of the difficulty lies in the complex processes that make up metabolism.

Researchers at the Sarah W. Stedman Center for Metabolism and Nutrition Research at Duke are working to uncover some of these answers.

The center was founded in 1988 as a research entity to study how nutrition impacts health. Today, under director Christopher Newgard, Ph.D., the Center has taken on a translational approach to metabolism and nutrition research, one that translates scientific discovery to new methods for treating obesity and related diseases.

“Our goal for the center was to build a group of strong basic sciences investigators in the general area of metabolism, build a clinical research capability, and to build a state-of-the-art analytical platform specifically designed for metabolic analysis,” Newgard said.

Currently, that group is composed of clinical investigators looking for nutritional interventions for common conditions such as obesity, high blood pressure and diabetes and researchers in the basic sciences investigating the biological mechanisms of weight and disease.

Laura Svetkey, M.D., director of clinical research, was instrumental in the landmark DASH (Dietary Approaches to Stop Hypertension) study, the first major study involving the Stedman center. The DASH study demonstrated that patients could help lower their blood pressure by simply increasing the amount of fruits, vegetables, and low-fat dairy they consumed, without weight loss or salt restriction and led to a nationwide change in dietary guidelines in 2005.

With this firm clinical foundation in place, it was up to Newgard, who came to Duke in 2002, to strengthen the center’s basic science approaches. Today, the Stedman Center is a leader in the translational field called metabolomics.

“Like the other major basic science initiatives to understanding human disease, such as genomics, that study on the level of the gene, metabolomics is the study of the concentration of small molecules that are the result of metabolic processes and make us who and what we are,” explained Newgard.

Metabolism refers to the set of chemical reactions in the body that sustain life, including the conversion of food into energy. Using instruments like mass spectrometers, scientists are able to quantitatively measure metabolites, or the chemicals created by the body’s metabolism, in organisms including humans. These metabolite readings can be used to create profiles that can be used to identify the molecular level differences between obese and lean people and that can potentially be used to predict the development of diseases associated with obesity. Center member Lillian Lien, M.D. is using metabolic profiling to predict who will lose weight and who will benefit from weight loss.

Newgard’s group and researchers Deborah Muoio, Ph.D., Dennis Thiele, Ph.D., Jeffrey Rathmell, Ph.D., and Jennifer Moss, Ph.D. are using the applied tools of metabolomics to determine the mechanisms of weight gain and the development of associated comorbidities, especially type II diabetes, which is predicted to affect 300 million people worldwide by 2020.

“I like to call it retro-translation,” said Newgard. “We’re making observations in humans and then we’re going backward to the animal models to test our hypotheses.”

In a review published in Nature Reviews: Molecular Cell Biology, Muoio and Newgard examine the metabolic mechanisms that lead to type 2 diabetes, mechanisms that involve the various affects of overeating and a lack of exercise on the body’s metabolism. So far, Muoio, Newgard, and others have revealed previously unappreciated mechanisms by which the food we eat leads to weight gain.

The Stedman Center’s research into the connections between metabolism and disease is bolstered by collaborations with clinical research departments throughout Duke Medicine. These include ongoing research projects with collaborations throughout Duke, such as the ones with Svati Shah, M.D, William Kraus, M.D., and Kristen Newby, M.D., in the division of cardiology and Elizabeth Hauser, Ph.D. in the section of medical genetics.

“Half of the world’s disease problems today are due to overnutrition and yet we know little about why. Do we understand what’s happening biochemically when obese individuals lose weight? By having that understanding, can we come up with new intervention strategies that allow obesity interventions to be sustained? A big problem with weight loss is weight rebound. Why is that?” said Newgard. Research at the Stedman center and in other departments is directly addressing these looming issues.

Svetkey also acknowledged the issue of weight regain after an initial successful loss. “A big issue is support,” said Svetkey, who is running further studies using the DASH diet to examine its effects on weight loss. In six -month long lifestyle change studies, patients in residence at the Stedman Center’s Center for Living location met in support groups every week. “People do a great job making a significant lifestyle change with this kind of support and encouragement,” she said. “It’s after that when people try to sustain the lifestyle changes that we know very little about how to help them do that. It’s very difficult to do and we live in an environment that’s really begging us to eat badly and too much. It’s going to take more research to learn how to help people withstand these societal forces.”