By Sandy Marvinney 

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.

Understanding blood sugar control through optogenetics: that’s what UW Medicine fellow Tom Meek, Ph.D., is pursuing. In the photo above, he and his mentor, Michael Schwartz, M.D., Res. ’86, Fel. ’90, take a look at his work and discuss a talk Meek is slated to give that week.
Photos: Clare McLean

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.”

Approximately one-third of the world’s people are overweight or obese.

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.

A Discovery

Another piece of the diabetes puzzle fell into place with the discovery of leptin in the 1990s. Leptin is a hormone made of fat cells, and insulin — in addition to regulating sugar — regulates fat storage. In uncontrolled diabetes, the body loses the ability to produce insulin. As a result, insulin stops regulating fat storage, fat starts to dissolve, and leptin levels plummet. In this condition, no matter how much is eaten, insulin and leptin levels will not rise.

Tom Meek, Ph.D., displays the light-emitting probe used to stimulate or inhibit neuronal activity.

One of Schwartz’s former post-doctoral fellows, Greg Morton, Ph.D., now on the faculty at UW Medicine, dove into leptin research. In 2010, he found that infusing very low doses of leptin directly into the brain of diabetic animals normalizes their blood sugar.

Schwartz tested a model of obese mice (ob/ob mice) that does not produce leptin and found that administering leptin shuts off the NPY neuron and reduces food intake. It became clear that the brain uses both insulin and leptin to adjust a mouse’s behavior to the metabolic needs of the animal. Schwartz and Morton then made a startling finding.

“We discovered that if you treat the brain of an uncontrolled diabetic rat that has low leptin and insulin with a small amount of leptin, you normalize not just the food intake, but also blood sugar, even though you are not giving them insulin,” Schwartz says.

When Schwartz and Morton first tried to publish this work, prestigious journals simply weren’t interested. The idea — that the brain could take on the role normally fulfilled by insulin — seemed completely off the wall. The findings were reproducible, however, and now researchers around the world consider them trailblazers in this line of research.

“It’s exciting because we were the first to demonstrate you can normalize blood sugar in the absence of insulin,” Schwartz says. “It opened a whole new window for us and a new research focus.”

From the Gut to the Brain

The new research focus also involved direct brain stimulation. And it involved another hormone, called FGF19.

Michael Schwartz, M.D., Res. ’86, Fel. ’90, and Thomas Meek, Ph.D., hope to publish their results in optogenetics sometime this year.

When an animal eats, the intestine makes FGF19, and about a decade ago, researchers at Eli Lilly found that injecting FGF19 either systemically or into the brains of ob/ob mice markedly improved their glucose tolerance. Morton took the research a step further. He found that injecting FGF19 into the brains of ob/ob mice dramatically improved glucose tolerance within 90 minutes by stimulating insulin-independent glucose disposal. The Journal of Clinical Investigation published the findings in 2013.

That next step, though — finding the neurons — is challenging. Neurons are tightly packed together, and it’s difficult to do research in a living animal and parse out which neurons are affected by what kinds of stimuli. Schwartz’s team, led by postdoctoral fellow Thomas Meek, Ph.D., may have found an answer: optogenetics. It’s a relatively new and highly specific tool, one in which light acts to turn neurons on or off.

The researcher injects a harmless virus — engineered to express the gene encoding a light-sensitive channel — into a mouse. The mouse, in its turn, has been bred to express a specific enzyme in a defined subset of neurons in the hypothalamus. After injection, the virus (which also contains a fluorescent marker) infects all neurons equally. However, only those neurons that express the enzyme will express the light-sensitive channel. When a researcher shines a light-emitting probe on those targeted neurons, the channel, reacting to the light, will either activate the neurons or inhibit them from firing. The glow of fluorescence marks the spot.

The idea ­­— that the brain could take on the role normally fulfilled by insulin ­— seemed completely off the wall.

In this case, Meek’s target is a subset of neurons packed into an area known as the ventromedial hypothalamic nucleus. He has shown that activating this subset of neurons provoked rapid blood-sugar elevation (a hallmark of diabetes). He also has made progress in neuronal mapping and has found a potential pathway for blood sugar control. Meek and Schwartz hope to publish their results sometime this year.

Beyond Insulin

Optogenetics will help the Schwartz Lab understand the neurocircuitry activated in diabetes; once it’s more thoroughly understood, there will be new opportunities to treat or prevent the disease — and perhaps to remedy other metabolic conditions, including weight gain.

Schwartz is sanguine about the promise of the research — especially for the millions of people worldwide affected by diabetes.

“It may be possible to target the neurocircuit with a designer protein to permanently change its function,” says Schwartz. “We might be able to treat patients by activating insulin-independent pathways that complement the action of insulin.”

Obesity and diabetes stats sourced from the World Health Organization and McKinsey Global Institute’s Overcoming Obesity report from Nov. 2014.

Connect With Us

Help us go green

Help us go green
Update your email address

Send a ClassNote

Send a ClassNote
Send an update

Write the editor

Write the editor
Tell us what you think

Make a Gift

UW Medicine UW School of Medicine

Box 358045, Seattle, WA 98195-8045 206.685.1875 | medalum@uw.edu