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Slow metabolism hindering weight loss? Genetic 'switch' may be answer

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Many who struggle with their weight will often blame a “slow” metabolism – meaning their bodies do not burn calories as quickly or as efficiently as others’.

For those who do suffer this condition, investigators from Beth Israel Deaconess Medical Center (BIDMC) say they have found a genetic “switch” that can accelerate a person’s basal metabolic rate – leading to a dramatic reduction in the risk for obesity and diabetes.

Their research, published in the journal Nature, involves turning off a gene that encodes a protein called nicotinamide N-methyltransferase (NNMT), which is found in the fat cells and the liver.  NNMT is known to process vitamin B3 and has been previously linked with certain types of cancers.

Lead researcher Dr. Barbara Kahn said she and her team first started looking at NNMT in relation to metabolism, after studying a major sugar transporter called GLUT4 in the fat cells of genetically engineered mice.  Through their work, they found that mice that produced large amounts of GLUT4 were insulin sensitive and protected against diabetes, while mice with no GLUT4 were insulin resistant and at risk for diabetes.

“So we took fat from mice with a lot of this sugar transporter and fat from mice without it, and we did something called a DNA microarray analysis,” Kahn, vice chair of the department of medicine at BIDMC and a professor of medicine at Harvard Medical School, told FoxNews.com. “We extracted the DNA from the fat tissue and analyzed levels of 16,000 genes at the same time ….And we found that the NNMT gene [and the GLUT4 transporter] were the most highly reciprocally regulated.” This means that the mice without the GLUT4 transporter had increased levels of NNMT.

Additionally, Kahn and her team analyzed a number of scientific databases and found that high levels of NNMT are often found in the fat cells of animals known to be insulin resistant.  Given these findings, the researchers decided to look at NNMT further, to see if manipulating the gene could affect an individual’s risk for diabetes and obesity.

In order to lower the expression of the NNMT gene, the researchers used antisense oligonucleotide (ASO) technology, which allowed them to interfere with the expression of the gene only in the fat cells and the liver. ASOs are short molecular strings of DNA, which can be designed to prevent the synthesis of specific proteins.

When the researchers turned off the NNMT gene in mice on high-fat diets, the mice did not gain as much weight compared to when the NNMT gene was functioning normally.  Furthermore, the mice did not change their eating or exercise habits, meaning the NNMT solely affected the mice’s basal metabolic rates.

According to Kahn, NNMT affects a biochemical mechanism known as a futile cycle, which plays a role in metabolic regulation.

“If we have an efficient metabolism, we don’t need many calories; the cells can get all the energy we need from a small number of calories,” Kahn said.  “If we have an inefficient metabolism, more calories get burned and we can eat more without gaining weight….But when we knock down this NNMT gene, we affect this [futile cycle].  We speed it up, and it will burn up more calories.” 

Ironically, a so-called “fast” metabolism is considered to be an inefficient one, Kahn noted.

More than 1/3 of adults in the United States are considered obese, and 25.8 million people – 8.3 percent of the American population – have diabetes, according to the Centers for Disease Control and Prevention.  While many health experts believe proper diet and exercise can help treat these conditions, others believe that genetics may also play a significant role in their development.

Kahn is hopeful that this new technique could be used to treat obesity, especially since ASOs have already been approved for use by the U.S. Food and Drug Administration for the treatment of conditions with other genetic causes – such as elevated cholesterol and hyperlipidemia. This means that clinical trials to test ASOs for anti-obesity therapy could move forward relatively quickly.

“We know that ASOs are safe and effective in people, so we would need to determine the safety and effectiveness of reducing NNMT levels in fat and liver in people long term,” Kahn said.  “When you knock down the NNMT gene in people, is that safe? Once that hurdle is over, it really could be explored for weight loss therapy.”

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