Searching for Effective Obesity Drugs

Despite years of dietary and lifestyle approaches to weight control, the prevalence of obesity in the United States is increasing rapidly. In an effort to understand weight gain, University of Washington researchers are studying not the stomach, but the brain.

One UW research team has discovered a signaling pathway within neurons that controls food intake. Another team has pinned down the role of a major hormone that stimulates hunger. These significant advances have helped build an increasingly comprehensive picture of the complex biochemistry that regulates body weight and appetite.

“Scientists have identified important drug targets and know enough about the regulatory system to attempt to predict how therapeutic designer drugs might act and how the system might compensate,” said Dr. Michael Schwartz, professor of medicine in the Division of Metabolism, Endocrinology and Nutrition. “I think it’s reasonable to expect that effective medications will be introduced within five years.”

The center of control is the arcuate nucleus in the hypothalamus, a part of the brain just above the stem. There, in response to long-term shifts in body-fat content, two sets of neurons are opposing levers in a balancing act. They generate distinct peptide molecules to stimulate or suppress appetite and energy expenditure.

Earlier work by Schwartz and colleague Dr. Denis Baskin, research professor of medicine, established that the main switches controlling both peptide neurotransmitters are two hormones, the levels of which rise or fall with the amount of body fat. These hormones are leptin, made primarily in the fat cells; and insulin, secreted from the pancreas. Insulin’s role in controlling blood sugar is well known. Leptin suppresses appetite.

Yet most obese individuals, it turns out, have plenty of leptin and insulin in their bloodstreams, up to five times more than normal levels. Somehow they are resistant to the actions of the hormones.

Seeking to overcome that resistance, Schwartz turned his research toward understanding the effects of leptin and insulin.

In a paper published in Nature, Schwartz’s lab identified the relevant signaling pathway within the nerve cells: When leptin binds to a neuron, it activates an enzyme, thereby setting in motion a series of biochemical responses that ultimately changes the cell’s electrical output. Later work showed that insulin uses the same enzyme pathway. Although insulin follows this pathway in tissues such as muscle or liver cells to regulate blood sugar levels, it had never been looked at in brain systems controlling body weight.

Research by Dr. David Cummings, assistant professor of medicine in the Division of Metabolism, Endocrinology and Nutrition, filled in a separate piece of the biochemical puzzle. While leptin and insulin are key hormones in the long-term regulatory system, they are not part of signaling the hunger that begins or satiety that ends individual meals.

In 2001, Cummings established that ghrelin, a hormone produced primarily by the stomach, may be an important mediator of mealtime hunger. Ghrelin levels rise before meals and fall after. It powerfully stimulates hunger when injected.

Follow-up work, published in The New England Journal of Medicine, showed that ghrelin levels are sharply elevated after weight loss, another instance of the kind of compensatory action that makes recidivism after dieting almost universal. The study also revealed flatline ghrelin levels in patients who have had gastric bypass surgery, by far the most effective current treatment for severe obesity.

Though this result suggests that drugs to block ghrelin might have an impact on weight management, understanding the entire system remains crucial.

“None of us believes that any single drug will be the cure-all for obesity,” Cummings said. “We have to identify all the molecules that play a critical role and develop classes of drugs to address each of these targets.”

Major pharmaceutical companies are funding a big commercial push to build upon this basic research and produce such breakthrough drug cocktails. Both Schwartz and Cummings anticipate that within five to ten years obesity, like high cholesterol or high blood pressure, will be routinely controlled with a daily regimen of drugs.