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Reduction of a Novel Energy-Regulating Target with Antisense Compound Protects against Diet-induced Weight Gain and Enhances Insulin Sensitivity

Study published April 10, 2014 in the journal Nature

Why are certain people able to eat as much as they want without gaining weight while others struggle to burn away the smallest about of calories they ingest? Most people attribute this phenomenon to one’s energy metabolism. However, exactly what controls a person’s energy metabolism is still not completely understood. In a research paper published by Isis and collaborators in the journal Nature1, a new piece of this puzzle is revealed. The answer lies in the amount of nicotinamide N-methyltransferase, or NNMT, an enzyme found in fat cells and the liver. While previous studies have shown an increase in NNMT in cancer and neurodegenerative diseases, its role in energy metabolism was not established.

In this study, Dr. Barbara Kahn’s lab at Harvard Medical School in collaboration with Isis discovered that NNMT levels were increased in the fat of mice prone to obesity or diabetes. To determine if the levels of NNMT contributed towards the development of obesity and diabetes, an antisense compound discovered by Isis that specifically reduced levels of NNMT was administered to mice fed on a high-fat diet. Mice treated with the antisense compound targeting NNMT showed a significant reduction in NNMT abundance when compared to mice not treated with a NNMT-targeting antisense drug. The reduction in NNMT protected these mice from diet-induced obesity as evidenced by a significant reduction in relative fat mass and an increase in relative lean mass. Further analysis showed that this reduction in weight gain on the high fat diet was not attributed to decreased food consumption but was instead caused by greater energy expenditure. This means that mice with lower NNMT levels were able to burn more of the calories they consumed. In addition to decreased fat gain, decreased NNMT also enhanced insulin sensitivity, reduced liver fat and decreased serum triglycerides and free fatty acids in mice treated with the antisense drug.

Together, these results suggest that NNMT plays a critical role in regulating energy metabolism and may also be involved in multiple metabolic functions. Isis antisense technology allows specific reduction of targets such as NNMT in selective tissues like liver and fat, thereby minimizing the potential for side effects. Using an antisense compound designed to target and reduce the production of NNMT, Isis enabled collaborators to uncover another promising target for the treatment of obesity and type 2 diabetes.

The journal article titled “Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity” is now available at Nature.

Reference
1Kraus et al. (2014) Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 508:258-262.

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