A drug first developed to treat Alzheimer’s disease reduces obesity and improves heart function.

A chemical inhibitor of the PDE9 enzyme stimulates cells to burn more fat. (CREDIT: Creative Commons)

Researchers at Johns Hopkins Medicine have found that a drug first developed to treat Alzheimer’s disease, schizophrenia and sickle cell anemia reduces obesity and fatty liver disease in mice and improves their heart function – without changes in diet or daily activities.

These findings, published in Journal of Clinical Research, show that a chemical inhibitor of the PDE9 enzyme stimulates cells to burn more fat. This happened in male mice and in female mice, in which sex hormone levels were lowered by ovariectomy, mimicking menopause. It is well known that postmenopausal women are at increased risk of obesity in the waist area, as well as the risk of cardiovascular and metabolic diseases.

PDE9 inhibition did not cause these changes in female mice that had ovaries, so female sex hormone status was important in the study.

“Currently, there is no proven effective pill to treat severe obesity, but such obesity is a global health problem that increases the risk of many other diseases,” says senior researcher David Kass, MD, Abraham and Virginia Weiss Professor. cardiology at the Johns Hopkins University School of Medicine. “What makes our findings exciting is that we have found an oral drug that activates fat burning in mice to reduce obesity and fat accumulation in organs such as the liver and heart that contribute to the disease; this is new.”

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This study follows work from the same lab in 2015, which showed for the first time that the enzyme PDE9 is present in the heart and contributes to heart disease caused by high blood pressure. Blocking PDE9 increases the amount of a small molecule known as cyclic GMP, which in turn controls many aspects of cell function throughout the body. PDE9 is the cousin of another protein called PDE5, which also controls cyclic GMP and is blocked by drugs like Viagra. PDE9 inhibitors are experimental, so there is no drug name yet.

After mice were placed on a high fat diet, mice were selected to either receive an oral PDE9 inhibitory drug or placebo. The PDE9 inhibitor reduced total body and liver fat in mice without changing diet or physical activity. However, placebo-treated mice continued to accumulate body fat and liver fat throughout the 6-8 week trial of the drug. (CREDIT: David Kass)

This study follows work from the same lab in 2015, which showed for the first time that the enzyme PDE9 is present in the heart and contributes to heart disease caused by high blood pressure. Blocking PDE9 increases the amount of a small molecule known as cyclic GMP, which in turn controls many aspects of cell function throughout the body. PDE9 is the cousin of another protein called PDE5, which also controls cyclic GMP and is blocked by drugs like Viagra. PDE9 inhibitors are experimental, so there is no drug name yet.

Based on these results, the researchers hypothesized that PDE9 inhibition could improve cardiometabolic syndrome (CMS), a constellation of common conditions including high blood pressure; high blood sugar, cholesterol and triglycerides; and excess body fat, especially around the waist. Medical experts consider CMS a pandemic and a major risk factor for heart disease, stroke, type 2 diabetes, cancer, and COVID-19.

Although PDE9 inhibitors remain experimental, they have been developed by several pharmaceutical companies and tested in humans for diseases such as Alzheimer’s disease and sickle cell anemia. The current study in mice used a PDE9 inhibitor manufactured by Pfizer Inc. (PF-04447943), which was first tested for Alzheimer’s but ultimately abandoned. Between the two registered clinical trials, more than 100 subjects received this drug and it was found to be well tolerated with no serious side effects. Another PDE9 inhibitor is currently being tested in human heart failure.

To test the effects of a PDE9 inhibitor on obesity and cardiometabolic syndrome, the researchers put mice on a high-fat diet, which resulted in doubling their body weight, high blood lipids, and diabetes after four months. A group of female mice had their ovaries surgically removed and most mice also had heart pressure applied to better mimic cardiometabolic syndrome. The mice were then given oral administration of either a PDE9 inhibitor or a placebo for the next six to eight weeks.

In female mice without ovaries (postmenopausal model), the difference in the median percentage change in weight between the drug and placebo groups was -27.5%, and in males -19.5%. Lean body mass did not change in either group, nor did daily food intake or physical activity. The PDE9 inhibitor lowered blood cholesterol and triglyceride levels and also reduced liver fat levels to levels seen in mice fed a normal diet. Heart condition also improved with PDE9 inhibition: ejection fraction (which measures the percentage of blood leaving the heart each time it beats) was relatively higher by 7-15%, and heart mass (hypertrophy) increased by 70% less compared to placebo. An increase in heart mass is indicative of abnormal cardiac stress. However, a decrease in this indicator by the inhibitor indicates that the load on the heart has decreased.

Researchers have found that PDE9 inhibition causes these effects by activating a major regulator of fat metabolism known as PPARa. By stimulating PPARa, levels of genes for proteins that control how fat is taken up by cells and used as fuel are greatly increased. When PPARa was blocked in cells or in the whole animal, the effects of PDE9 inhibition on obesity and fat burning were also lost. They found that estrogen usually plays the role of PPARa in fat regulation in women, but when levels drop, as it does after menopause, PPARa becomes more important in fat regulation, and therefore PDE9 inhibition has a greater effect.

“The finding that the experimental drug did not help female mice that had ovaries shows that these sex hormones, especially estrogen, have already achieved what PDE9 inhibition does to stimulate fat burning,” notes Sumita Mishra, a researcher who did most of the research. Job. “Menopause lowers sex hormone levels and their control of fat metabolism then switches to a PDE9-regulated protein, so drug treatment is now effective.”

According to the US Centers for Disease Control and Prevention, more than 40% of people living in the US are obese; and 43% of American women over 60—long past menopause—are considered obese.

Kass notes that if his lab results in mice apply to humans, then a 250-pound person could lose about 50 pounds with an oral PDE9 inhibitor without changing their eating or exercise habits.

“I’m not suggesting sitting on the couch and taking pills, but I suspect that when combined with diet and exercise, the effect of PDE9 inhibition could be even stronger,” Kass says. The next step will be human testing to see if PDE9 inhibitors cause similar effects in men and postmenopausal women.

“PDE9 inhibitors are already being studied in humans, so clinical studies on obesity are just around the corner,” Kass says.

To learn more about science and technology, visit our New Innovations section at The bright side of the news.

Note: Materials provided above by Johns Hopkins Medicine. Content can be edited for style and length.

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