Some people are lean, others more Rubenesque. Ron Evans has discovered that, to some degree, the difference between a couch potato and a marathon runner lies in the activity of a family of genes that control the storage and burning of fat. By exploring the function of these key regulatory genes, Evans hopes to deepen our understanding of the molecular basis of obesity-related diseases such as diabetes and syndrome X, a disorder characterized by high blood pressure, heart disease, and insulin resistance. Ultimately his studies could lead to the development of drugs that might help people slim down and improve their overall health.
Evans was hooked on science from the start. "I was a real lab rat," he says of his early days at the bench. "Fifteen- or 16-hour days were pretty normal. It was work, work, work—and I loved it." As a postdoctoral fellow at the Rockefeller University, Evans focused his energies on studying a problem that would hold his interest throughout the rest of his career: how cells control the activity of their genes, a process central to life. In particular, he wanted to determine how the growth hormone gene is regulated by steroids and thyroid hormone. Researchers believed that the receptor proteins that recognize these hormones could function as genetic switches that control gene activity.
Using techniques that were then at the forefront of molecular biology, Evans isolated the growth hormone gene, which he brought with him to the Salk Institute where he started his own lab. With the gene in hand, Evans set out to identify the switches that turn it on. In rapid succession, he and his colleagues discovered several receptors capable of regulating the gene for growth hormone—and other genes. Each works in a similar way. It binds to some sort of activating molecule—a hormone or vitamin—and then heads for the nucleus, where it tweaks the activity of its target gene. Because these receptors share a common mechanism, they form a "nuclear receptor superfamily."
To date Evans has turned up nearly 50 receptors that are part of this nuclear receptor superfamily. Two of these receptors, PPARγ and PPARδ, play key roles in regulating the storage and burning of fat. PPARγ snatches fat from the blood and squirrels it away inside fat cells. Its sister protein, PPARδ, regulates how muscles burn fat. When kept on a high-fat diet, mice that lack PPARδ become obese. Mice that are engineered to produce an overactive version of the receptor in their muscle tissue remain sleek and lean. PPARδ revs up cellular fat-burning pathways and beefs up the animals' slow-twitch muscle mass. And 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.
Evans and his crew are now focused on trying to understand how these nuclear receptors work—and how their misbehavior can lead to disease, including high blood pressure, obesity, diabetes, and cancer.
Dr. Evans is also Professor in the Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute for Biological Studies in La Jolla, California.
RESEARCH ABSTRACT SUMMARY:
The discovery of steroid receptors and, subsequently, the family of orphan nuclear receptors provides a molecular approach to the study of metabolic regulation by fat-soluble hormones, vitamins, and dietary lipids. Ronald Evans is interested in the origins of physiology and the molecular genetics of muscle performance, metabolic disease, inflammation (including atherosclerosis and diabetes), and cancer and using this information to devise small-molecule therapy.
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Photo: Marc Lieberman/Salk Institute