Ten thousand years ago nobody was eating a five-course steak dinner beginning with an appetizer of deep-fried cheese sticks. Until recently, the threat to a person's survival was not from overeating, but rather from undereating. For millions of years, people with a rich supply of genes predisposing them to eat a lot and gain weight would have survived famines and enjoyed an evolutionary advantage.

These days most Americans have access to a continuous source of highly palatable, highly caloric foods. This environment, combined with a gene pool selected for overeating, has resulted in an obesity epidemic. Our gastronomic options have changed, but our genetic adaptations have not caught up.

Body weight is a polygenic trait, which unlike eye color, is determined by many genes. As with other polygenic traits, such as blood pressure and cholesterol levels, researchers would like to offer doctors multiple clinical options to alter body weight.

"At least 60 to 70 percent of the factors governing body weight are genetic--the rest is determined by one's environment," says Dr. David Cummings, assistant professor of medicine in the Division of Metabolism, Endocrinology and Nutrition. "While it's helpful to do what you can with diet and exercise, the body-weight ballpark in which you live is dictated by the assortment of genes you inherited from your parents."

Cummings and his lab are interested in how the brain senses body weight and how it adjusts appetite and metabolic rate to keep an individual in his or her set range. Every individual has a personal set range depending on his or her constellation of genes.

Willed behavior allows people to move to the bottom or top of their range, but it cannot change the genetically programmed parameters of the range. Theoretically, body-weight range could be altered by modifying genes in people who received an unlucky genetic shuffle of the cards.

"This is why dieting is so difficult," says Cummings. "In general, dieting doesn't work over the long haul. Your brain is sensitive to how fat you are. If you get much heavier or much lighter than your set range, your brain will invoke changes in appetite and metabolic rate to bring you back."

In particular Cummings would like to elucidate the mechanisms responsible for turning those brain signals off and on. The strategy is to target critical chemical pathways in the hypothalamus, the food-intake governing center of the brain.

Body weight is held in place by a highly redundant group of hypothalamic neuropeptides, molecules produced primarily in the hypothalamus. It turns out that almost all of the neuropeptides that signal satiety do so by stimulating an enzyme called protein kinase A (PKA); those that signal hunger all suppress PKA. Cummings and Ph.D. candidate Leah Selfridge are looking for a way to mimic signaling from all of the satiety neuropeptides by stimulating hypothalamic PKA using drugs called phosphodiesterase (PDE) inhibitors. Many current medicines with acceptable side effects, such as antidepressants, cardiac stimulators and Viagra, inhibit specific PDEs.

"PDEs come in many different flavors," says Cummings. "The goal is to find a PDE that is expressed in the hypothalamus and block it to alter hunger signals."

Preliminary experiments in rats showed that a Class 1 PDE inhibitor enhanced the potency of leptin, a satiety protein that crosses the blood-brain barrier and indicates to the brain the amount of body fat. The PDE inhibitor is a potential candidate for causing leptin to work at lower levels.

This process is similar to what's happening in people with type 2 diabetes. A type 2 diabetic has lots of insulin in his or her system, the insulin just doesn't work very well. In most obese people there is plenty of leptin produced by fat tissue, but the brain is relatively insensitive to it.

Cummings has also begun work on the recently discovered molecule ghrelin, with the help of UW medical student Karin Schmidova. This peptide is an appetite stimulant produced by the stomach and possibly the brain.

"When you become hungry at lunch time, it's probably not because your leptin levels have fallen," says Cummings. "And there's no significant change in your body weight between eight in the morning and noon. In fact, leptin levels gradually increase over the course of the day. Ghrelin is a potential candidate for the meal-to-meal hunger stimulus."

Together with Dr. Brent Wisse, senior fellow in medicine, Cummings is also trying to understand the causes of pathological anorexia and weight loss such as occur in cancer patients. This work, still in the preclinical stage, is with prostate cancer.

"If we understand the mechanisms of wasting, not only could we potentially cure it, but we might also be able to harness those mechanisms and use them to treat obesity," explains Cummings. "For example, if molecule X is secreted by a tumor and causes a loss of appetite, then you could develop an antagonist against X to treat cancer anorexia, and a lookalike of X to use for obese people."

Cummings hypothesizes that cancer cells produce multiple molecules that suppress appetite, resulting in anorexia. He's looking for the single biochemical pathway where these molecules converge to communicate with the brain. That pathway would be a logical target for drug therapy.

"Research on body-weight regulation is now about where blood pressure or cholesterol research was a couple of decades ago," says Cummings. "At that time there were only one or two choices for treatment. Now there are many more options for doctors treating high blood pressure and cholesterol. In the next decade it's quite possible that not one but several new treatments for obesity will appear in the marketplace."

Cummings received his M.D. cum laude from Harvard Medical School/Massachusetts Institute of Technology in 1987. He completed an internship and residency in the UW affiliated hospitals. From 1990 to 1991 Cummings was the chief medical resident at the Seattle VA Medical Center. In 1993 he was a senior fellow in the UW Division of Metabolism, Endocrinology and Nutrition and the Department of Pharmacology. He has received a National Institutes of Health Physician-Scientist Award and a Burroughs-Wellcome Fund Career Award. Cummings joined the School of Medicine faculty in 1998 as an assistant professor. He works closely with research asistant Scott Frayo on all of his projects.