Making Obese Mice Slim, Without Diet or Exercise

WEDNESDAY June 3, 2009 -- Researchers have come up with two new ways to control weight and blood sugar levels in obese mice -- without diet or exercise.

And although putting the techniques to use in people is a long way off, they hope the research will help in the development of drugs that could be used to treat obesity or type 2 diabetes.

The findings appear in two studies in the June issue of Cell Metabolism.

In one of the studies, researchers inserted a molecular shunt into the liver cells of 94 mice.

Despite chowing down on high-fat foods that mimicked a human fast-food diet, the mice with the genetically engineered shunts stayed skinny, compared with mice without the shunts.

The shunt, which contained an enzyme normally found in bacteria and plants but not in mammals, acted as an "artificial engine" that enabled liver cells to burn more fat.

Instead of accumulating in the blood or being stored by the body, the fat was metabolized, converted to carbon dioxide and exhaled.

"Exercise is always a good way to burn fat, but we found you can increase the metabolic channels for burning fat even without exercising more," said study author James Liao, a professor of chemical and biomolecular engineering at the University of California, Los Angeles.

Dr. Stuart Weiss, an endocrinologist at New York University Langone Medical Center, said the concept of boosting the liver's ability to burn energy without stepping up physical activity is intriguing.

"The idea that we can use this shunt pathway to manipulate fatty acid metabolism in the liver is very exciting as a basic science question," Weiss said.

Still, genetic engineering has not yet been used to successfully treat people, so any anti-obesity treatments using molecular shunts are years away, Liao said.

In the other study, researchers were able to restore blood glucose levels in obese, severely diabetic mice to normal -- again without changing their diets or activity levels.

The mice in the study lacked leptin and receptors in the brain for leptin, a hormone that is involved with many bodily functions, including regulating appetite and metabolism. As a result, the mice became morbidly obese and diabetic.

When researchers added leptin receptors to a particular type of neuron (pro-opiomelanocortin neurons) in the hypothalamus of the mice's brains, their blood glucose levels dropped to normal.

The mice, which had previously lain around all day, became more active. They also ate 30 percent fewer calories and lost a little weight, though the drop in blood glucose levels was independent of that, the study found.

"This gives us the opportunity to search for drugs that might induce the desire or will to voluntarily exercise," said study author Christian Bjorbaek, an associate professor of medicine at Harvard Medical School.

Figuring out how to use leptin to help humans struggling with obesity has proven elusive.

More than 15 years ago, there was a flurry of excitement when studies in mice showed that giving them leptin caused them to lose their body fat, Bjorbaek said.

But later research found that obese people don't lack sufficient leptin. For reasons not fully understood, their cells are resistant to it.

Researchers hope their study will provide clues about ways to develop drugs to target neurons or other pathways in which leptin plays a key role.

"The hope is there will be new drugs that would target the neurons or the downstream pathways of the neurons to help control blood glucose in people who suffer from type 2 diabetes and who are obese," Bjorbaek said.

Weiss said the study sheds more light on the complex mechanisms controlling weight, blood sugar, appetite and physical activity.

"There are many different hormones and parts of the brain that are involved in regulating appetite, exercise and activity," Weiss said. "It's a concert and an orchestra. The goal is to be able to understand this system well enough to manipulate it so obesity and diabetes can be avoided."

Until then, watching what you eat and exercising remains the best means of staying slim, lowering blood glucose and preventing diabetes.

"Until we get a very clear understanding of the way that all of these compounds work together, we need to accept the fact that diet and exercise is the only well-proven, safe, side effect-free approach to weight and glucose control," Weiss said.

More information

The U.S. National Heart, Lung, and Blood Institute has more on overweight and obesity.

Posted: June 2009


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