An experimental drug once studied for Alzheimer’s disease and other conditions may have an unexpected use: helping the body fight obesity.
Researchers at Johns Hopkins Medicine found that the treatment produced striking metabolic benefits in mice without requiring them to eat less or become more physically active.
The findings could eventually point to another way of treating obesity and some of the health problems that often come with it.
However, the results are from animal experiments, so researchers still need to determine whether the same effects occur in people.
Obesity is much more than a matter of body weight. Excess body fat can raise the risk of type 2 diabetes, high blood pressure, fatty liver disease, heart disease and several other chronic conditions.
For many people, losing a large amount of weight and keeping it off is difficult. The body has powerful systems that regulate hunger, energy use and fat storage, which can work against long-term weight loss.
The Johns Hopkins team studied an enzyme called PDE9. Enzymes are proteins that help control chemical reactions in the body, and PDE9 affects the amount of a signaling molecule called cyclic GMP inside cells.
Cyclic GMP helps cells communicate and influences several processes in the heart and other tissues. PDE9 breaks down this molecule, so blocking the enzyme allows cyclic GMP signals to remain active for longer.
PDE9 belongs to the same broad enzyme family as PDE5. PDE5 is better known because it is targeted by sildenafil, the medicine sold as Viagra, although PDE9 and PDE5 have different roles in the body.
Researchers had previously become interested in PDE9 because of its effects on the heart. In work published in 2015, the Johns Hopkins team found that PDE9 was present in heart tissue and could contribute to heart problems associated with high blood pressure.
The scientists then wondered whether blocking PDE9 might affect a wider group of metabolic problems. These include obesity, high blood sugar, unhealthy cholesterol levels and high blood pressure, which often occur together.
For the new research, the team used a PDE9-blocking compound called PF-04447943. The drug was developed by Pfizer and had previously been investigated as a possible treatment for Alzheimer’s disease.
Although development for Alzheimer’s disease was discontinued, the compound had already been tested in more than 100 people. Those earlier trials provided useful information suggesting that the drug could be given to humans without major safety problems under the conditions studied.
In the obesity experiments, researchers gave the PDE9 inhibitor to mice and observed substantial changes. The treated animals lost excess weight and showed improvements in fatty liver and heart health.
What made the findings especially interesting was that the animals did not need to change how much they ate or how active they were. This suggests that the drug may have changed the way their bodies used and stored energy rather than simply suppressing appetite.
The researchers found evidence that blocking PDE9 increased the burning of fat. The effect was particularly notable in female mice and in animals whose biology produced lower levels of estrogen.
This could potentially be important for older women because estrogen levels fall after menopause. Weight gain and changes in where fat is stored are common during this period, while the risks of diabetes and cardiovascular disease also rise with age.
The researchers suggested that if the size of the weight-loss effect seen in mice could eventually be reproduced in humans, it might be substantial. But estimates such as a 250-pound person losing around 50 pounds are theoretical and should not be interpreted as a demonstrated result in people.
No clinical trial has yet shown that a PDE9 inhibitor produces this degree of weight loss in people with obesity. Animal studies are useful for discovering biological mechanisms, but many treatments that work well in mice ultimately produce different results in humans.
The potential value of the approach also goes beyond the number on a scale. Improvements in fatty liver and heart function suggest that changing PDE9 activity could influence several biological problems linked to obesity.
That could make the pathway interesting for researchers studying metabolic syndrome. Metabolic syndrome refers to a group of conditions, including high blood pressure, high blood sugar and unhealthy blood fat levels, that together increase the risk of heart disease and diabetes.
The research also provides another example of drug repurposing. A medicine developed for one disease can sometimes turn out to affect a biological pathway that is useful for treating a completely different condition.
Other PDE9 inhibitors have been investigated for diseases including heart failure, schizophrenia and sickle cell disease. This existing research could help scientists understand the safety of the drug class as they consider possible new uses.
Still, much more work is necessary before PDE9 inhibitors could be considered an obesity treatment. Researchers need human trials specifically designed to test weight loss, metabolic health, appropriate doses, long-term safety and possible side effects.
The study was led by Dr. David Kass of Johns Hopkins Medicine and was published in the Journal of Clinical Investigation. The findings offer an intriguing new direction for obesity research, but they should be viewed as an early step toward a possible treatment rather than evidence of a weight-loss pill ready for patients.
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