About 2.1 billion people worldwide — approximately one-third the population — are overweight or obese.
Without interventions, almost half the world’s adults could be overweight or obese by 2030.
It’s not only an unhealthy trend; it’s a deadly and costly one. Each year, approximately 2.8 million people die from causes attributable to a high body mass index. In economic impact, medical costs related to weight total approximately $2 trillion annually, only slightly trailing cigarette smoking and armed violence. Diabetes, closely linked to obesity, is also on the rise — killing about 1.5 million adults annually.
The causes of these complex metabolic disorders are not fully understood. Management is challenging, and cures are elusive. To deepen our understanding, UW Medicine researchers have been looking beyond the digestive tract and traditional knowledge of glucose metabolism. They’re moving up: from the gut to critical neuron centers in the brain. And they’ve made discoveries that may, eventually, change how diabetes is treated and weight gain controlled.
Defending your body weight
Normal animals, including humans, “defend” a particular body weight. Decades ago, studies revealed that animals deprived of food will eat more than normal to catch up, a process called hyperphagia. Once body weight returns to normal, food intake normalizes, too.
“In obesity, the control circuity is defective, and the defended body weight is elevated,” says UW Professor Michael Schwartz, M.D., Res. ’86, Fel. ’90, director of the Diabetes and Obesity Center of Excellence and holder of the Robert H. Williams Endowed Chair in Medicine. “That’s why only a small percentage of overweight people trying to lose weight are able to keep it off long term.”
Schwartz and his team are pioneers in investigating how brain mechanisms govern food intake, energy balance and glucose metabolism, and how impairments in these systems can lead to obesity and diabetes. Twenty years of research to arrange the puzzle pieces is now paying off in findings that could lead to development of paradigm-shifting treatments.
Brain neurons and feeding behavior
First, a little research history. During the 1990s, Schwartz and his team posed a new question about the food-intake process: when an animal is in a fasting state, how does the body signal the brain to begin hyperphagia, or “catch-up” eating? They thought a drop in insulin, which stimulates hunger and eating to raise eating levels, might be that signal. Studies elsewhere indicated that fasting activated a set of neuropeptide Y (NPY) neurons in the hypothalamus, and that treating rats with NPY stimulated feeding.
In an early experiment, Schwartz found that infusing the brains of fasting rats with insulin blocked the activation of NPY neurons. As a result, the hungry rats showed markedly less interest in eating. “It was the first link in the chain between the action of a peripheral hormone and a change in the neural circuit that was related to feeding behavior,” Schwartz says.
In the 93 years since insulin was first used to treat diabetes, thousands of papers have been published on its role in glucose metabolism. “All tissues need glucose, and it was assumed that when blood sugar rises, insulin-sensitive tissues clear some of that sugar from the body, and other tissues passively take it up,” Schwartz says. “It’s been known for decades that insulin explains only about 50 percent of glucose metabolism. The other 50 percent has been below the radar screen.”
Exploring below the radar became the mission of Schwartz’s 20-member research team.