A drug first studied for brain disorders may have an unexpected use in obesity, according to research from Johns Hopkins Medicine.
In experiments with mice, the medicine reduced body fat and improved several health problems linked to obesity without requiring the animals to eat less or exercise more.
Obesity is a complex long-term disease that affects hundreds of millions of people worldwide. Carrying too much body fat can increase the risk of type 2 diabetes, heart disease, high blood pressure, fatty liver disease and other serious health problems.
Scientists have made major progress in obesity treatment in recent years, including the development of highly effective injectable medicines. However, researchers continue to search for additional treatments, including convenient oral drugs that work through different biological pathways.
The Johns Hopkins team studied a group of drugs called PDE9 inhibitors. These medicines block an enzyme called phosphodiesterase 9, or PDE9, which helps control chemical signals inside cells.
PDE9 affects a signaling molecule called cyclic GMP. This molecule is involved in many processes throughout the body, including blood vessel function, heart activity and the way cells use and store energy.
The researchers had previously studied PDE9 in heart disease. In 2015, their work suggested that blocking the enzyme could protect the heart from damage associated with high blood pressure.
That discovery led the team to ask a broader question. Could blocking PDE9 also change metabolism and help the body handle excess fat?
To investigate, the scientists tested a PDE9-blocking drug called PF-04447943 in mice. The medicine had originally been developed by Pfizer and studied as a possible treatment for Alzheimer’s disease.
Although it was not successful as an Alzheimer’s treatment, earlier human testing provided useful information about how people tolerated the drug. This made the compound interesting to researchers looking for other possible uses.
In the mouse experiments, blocking PDE9 produced striking metabolic changes. The treated animals lost body fat even though researchers did not require them to reduce their food intake or increase physical activity.
The treatment also reduced fat buildup in the liver. Fatty liver is common in people with obesity and can sometimes progress to inflammation, liver scarring and more serious liver disease.
The researchers also reported improvements in heart function and several measures related to metabolism. These findings suggest that PDE9 may influence how the body stores and uses energy rather than acting simply by suppressing appetite.
One interesting part of the study involved sex differences. The weight-loss effect was particularly strong in female mice that no longer produced normal levels of estrogen, a situation designed to resemble some biological changes that occur after menopause.
This could be important because body composition and metabolism often change after menopause. However, results in a mouse model cannot tell doctors whether postmenopausal women would experience the same response.
The researchers estimated that if the size of the effect translated directly to humans, it could represent substantial weight loss. But such comparisons are theoretical and should not be interpreted as evidence that a person taking the drug would lose a specific number of pounds.
Animal studies are an early step in drug development. Many treatments that produce impressive results in mice later turn out to be less effective, ineffective or unsuitable when tested in people.
The study also should not be interpreted to mean that diet and physical activity are unimportant in obesity. Body weight is influenced by a complicated combination of biology, genetics, environment, medications, sleep, food availability, activity and other factors.
What the research does show is that obesity cannot always be explained simply as a failure of willpower or excessive eating. Biological systems that control energy use and fat storage can strongly influence how easily a person gains or loses weight.
The study was led by Dr. David Kass and colleagues at Johns Hopkins Medicine and was published in the Journal of Clinical Investigation. It identifies PDE9 as a possible target for future obesity treatments and provides a reason to investigate existing PDE9 inhibitors in new ways.
One advantage is that some drugs targeting PDE9 have already been tested in humans for other diseases. Still, previous safety information does not prove that long-term treatment would be safe for people with obesity or that doses needed for weight loss would be appropriate.
Clinical trials would need to determine whether PDE9 inhibitors actually reduce weight in people, which patients benefit most, how long the effect lasts and whether there are important side effects. Researchers would also need to compare them with the increasingly effective obesity medicines already available.
For now, the findings are promising laboratory evidence rather than a new weight-loss prescription. If future human trials confirm the metabolic benefits, however, blocking PDE9 could provide scientists with another way to treat obesity and some of the heart and liver problems that often accompany it.
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