Obesity-Related Enzyme Targeted in Mouse Study

WEDNESDAY April 9, 2014, 2014 -- An enzyme in the fat and liver of mice could take a key role in future attempts to battle obesity and type 2 diabetes, according to a new study.

The enzyme -- nicotinamide N-methyltransferase, or NNMT -- appears to help regulate the ability of cells to burn energy efficiently, researchers report.

By hampering the gene that produces the enzyme, researchers were able to keep mice fed a high-fat diet from gaining weight. The mice also became better at using insulin to process blood sugar, which could lower their odds for developing diabetes.

"The mice were eating normally. It wasn't a food intake effect. They actually had increased energy expenditure," said senior author Dr. Barbara Kahn, vice chair of medicine at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School. "For every calorie they ate, they burned up more energy."

Controlling levels of this enzyme could potentially help people reach and maintain a healthy weight by prompting the body to burn excess energy rather than store it, Kahn suggested.

"Diet and exercise will always be very key, but this opens up the possibility of a new way to speed up cellular metabolism so people don't store as much fat," she said.

Results of animal research do not necessarily apply to humans, however.

Kahn and her colleagues discovered this new role for the enzyme while researching the role of body fat in the development of type 2 diabetes.

Researchers studied thousands of genes present in the fat of mice to determine which ones affected the body's ability to convert glucose (blood sugar) into cellular energy, Kahn said.

The investigators found large amounts of the NNMT enzyme in the fat of mice prone to obesity or diabetes because they used glucose less efficiently and tended to store it away in body fat. This enzyme is already known, but no one has linked it to cellular metabolism, Kahn said.

To test the enzyme's role in weight gain, researchers used a targeted genetic medication in the mice being served a high-fat diet to "knock down" the gene that promotes production of the enzyme.

Reducing levels of the enzyme in their fat and liver protected mice from diet-induced obesity, causing a 47 percent reduction in their body fat and a 15 percent increase in their lean body mass, the researchers report in the April 10 issue of the journal Nature.

Mice with reduced levels of this enzyme also experienced a 50 percent to 60 percent reduction in their blood insulin levels, an indication of improved insulin sensitivity.

Further, the medication worked without causing any harmful side effects, Kahn said.

Researchers believe the enzyme influences metabolism by suppressing a biochemical process known as a "futile cycle," in which cellular reactions are sped up and burn more energy.

"We all know people who can seemingly eat whatever they want and not gain weight," said Kahn. "Part of the reason for this natural weight control owes to basal cellular metabolism -- the body's inherent rate of burning energy. A futile cycle is one way to speed up energy utilization in cells."

The explanation makes sense in an evolutionary sense, she said. Critters facing starvation need an enzyme like this to improve their ability to store away what little food energy they find, she explained.

"Human beings have evolved to have efficient metabolisms so they could survive famines and droughts, and times when food was not available," Kahn said. "A person with a more efficient metabolism is more likely to gain weight than a person with a less efficient metabolism."

Don't expect this new finding to be translated into a weight-control treatment for humans anytime soon, however, experts said.

"One cannot be assured that this will be a totally healthy thing to do," said Charles Brenner, a professor of biochemistry and internal medicine at the University of Iowa Carver College of Medicine. "We don't know what side effects this approach would have. The ability to gain weight on a high-fat diet is a normal part of animal metabolism." Interfering with this natural process could have unintended consequences, he noted.

Brenner added that the new research only tested the ability to prevent weight gain by reducing the enzyme's levels in mice. "They did not use this drug as a weight-loss measure," he said.

Even more skeptical is Dr. Christoph Buettner of the Icahn School of Medicine at Mount Sinai in New York City.

"Most of these kinds of discoveries do not lead to new drugs for one reason or another," Buettner said. "Even if successful, it will take close to a decade until a drug targeting NNMT reaches our clinics."

More information

For more information on obesity, visit the U.S. National Library of Medicine.

Posted: April 2014


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