The magazines make it sound easy: Ditch your daily donut and lose five pounds in a month. Swap your breakfast burrito for bran and fit into your swimsuit by summer. Few would dispute that the contents of our lunch box influence the size of our jeans. Yet when it comes to figuring out a formula for weight loss — or for achieving any other changes in our body composition — there are no predictable calculations, said Dr. Marc Van Gilst, a new member of the Basic Sciences Division.
"It's long been thought that the body's metabolic pathways were well understood," said Van Gilst, who joined the Center in September. "But now, we're beginning to learn that metabolic pathways aren't fixed — they're flexible. They can be rearranged in response to conditions that our bodies are unfamiliar with, such as changes in diet or physical activity, which makes it hard to predict how the body will respond."
As an example, he points to the row of empty Coke cans that line his desk. "Based on the number of calories in a can of Coke and the number of calories needed to gain a pound, I figure I consume about 50 pounds worth a year. But if I stop drinking my usual three cans of Coke a day, I won't weigh 50 pounds less next year," said Van Gilst, whose own physique doesn't appear to have an extra pound to spare. "Our body adjusts to lower calories. Though it will make a difference if you diet, your body will compensate in some way to fight it."
Nuclear hormone receptors
The body's response to what we ingest — including fats, nutrients, toxins and drugs — influences much more than our ability to stay slim. According to Van Gilst, our metabolism's ability to manage our dietary intake is essential for healthy development and longevity, and glitches in the system can lead to serious diseases like diabetes and even cancer.
As a way to untangle the vast web of metabolic pathways that mobilize in response to diet, Van Gilst's research focuses on the molecules that are likely to be the lynchpins of the system: a family of proteins that both sense nutrients in the environment and then relay signals to stimulate or dampen the activity of enzymes that digest, store or detoxify the compounds. These dual-function proteins — known as nuclear hormone receptors because a subset of them also respond to hormones — are of great interest to scientists, in part, for their ability to yield fundamental insight into the body's response to nutrients. Some nuclear hormone receptors may also be potential drug targets for diseases like diabetes, obesity, cancer or other conditions in which metabolism has gone awry.
Though the topic of dietary intake and metabolism is of great relevance to human health, Van Gilst's research subject of choice is a laboratory animal that is not particularly known for its gastronomic sophistication. But by opting to focus on the microscopic soil worm Caenorhabditis elegans for his studies, Van Gilst gains the ability to apply the power of genetics to an organism that — despite its apparent simplicity — uses nutrient signaling and response systems that are nearly identical to humans.
"The worm is like a miniature liver," said Van Gilst, referring to the organ's importance in digestion and detoxification. "The worm also has many more nuclear hormone receptors than humans — probably because it confronts a very diverse assortment of foods, chemicals and toxins in its native environment. That makes it a very powerful system for studying sensing and signaling networks."
Dr. Jim Roberts, director of the Basic Sciences Division, said that the Center was fortunate to attract Van Gilst as a faculty member.
"Marc stood as the top candidate among a group of more than 400 applicants for a new assistant member position," he said. "He received numerous job offers from institutions around the country, and we are very fortunate he chose to come here. He is using molecular genomics in a model organism and applying it in a very creative way to an important problem that affects all of us. He will be a terrific colleague and a fantastic addition to the Center."
Metabolism and nhr-49
Van Gilst began this project as a postdoctoral fellow in Dr. Keith Yamamoto's lab at the University of California, San Francisco. There, he identified a particular nuclear hormone receptor called nhr-49, which modulates the worm's fat usage in response to what it eats as well as its response to starvation. Those experiments revealed a surprising connection between fat metabolism and longevity, demonstrating that worms with a body composition high in saturated fat have a shorter-than-normal lifespan.
In his own lab at the Center, he will continue to characterize nhr-49's role in metabolism. Humans possess a receptor analogous to nhr-49, mutations in which have been linked to diabetes — a potentially deadly metabolic disease in which the body fails in its attempt to balance its metabolism of sugars and fats. He also plans to identify other worm nuclear hormone receptors involved in sensing nutrients and toxic compounds.
Van Gilst speculates that worms may have evolved such a large number of nuclear hormone receptors because they are confined to a relatively slow-moving existence in the soil. "They can't decide what to eat," he said. "So their bodies have to deal with all kinds of nutrients and toxins."
Even humans, who have the luxury of thousands of choices in the supermarket, must cope with digesting less-than-ideal ingredients. "Plants are filled with naturally occurring compounds that are toxic to us," he said. "People are worried about ingesting pesticides — but it turns out that many fruits and vegetables naturally produce their own pesticides, which can be toxic or even carcinogenic compounds, which our bodies must detoxify. Plants didn't evolve to be nutritious to humans."
Although Van Gilst's work to define the molecular underpinnings of metabolic flexibility is a novel approach in this emerging field, the interplay of diet and human diseases, particularly cancer, is a major focus at the Center. Van Gilst looks forward to establishing connections with researchers with related research interests who study the problem from different angles.
He is delighted to be a part of the Basic Sciences Division and its highly collegial atmosphere.
"I knew a lot about the excellent scientific reputation of the division when I applied for the position," he said. "But I had no idea about how interactive and democratic the group is. I'm really happy to be here."