Viagra-related Drug Reduces Obesity: Study

Viagra-related drug, a chemical inhibitor of the enzyme PDE9, found to stimulate fat burning process, as per the findings published in the Journal of Clinical Investigation.

This occurred in male mice and in female mice whose sex hormones were reduced by removing their ovaries, mimicking menopause. Inhibiting PDE9 did not cause these changes in female mice that had their ovaries, so female sex hormone status was important in the study.

‘Combining diet and exercise along with PDE9 inhibition may be even greater for reducing body weight in obese people.’

"Currently, there isn't a pill that has been proven effective for treating severe obesity, yet such obesity is a global health problem that increases the risk of many other diseases," says senior investigator David Kass, M.D., Abraham and Virginia Weiss Professor of Cardiology at the Johns Hopkins University School of Medicine.

"What makes our findings exciting is that we found an oral medication that activates fat-burning in mice to reduce obesity and fat buildup in organs like the liver and heart that contribute to disease; this is new."

In 2015 researchers first showed the PDE9 enzyme is present in the heart and contributes to heart disease triggered 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 enzyme cousin of another protein called PDE5, and is blocked by drugs like Viagra. Based on the results, the investigators suspected PDE9 inhibition might improve cardiometabolic syndrome (CMS).

The current mouse study used a PDE9 inhibitor made by Pfizer Inc. (PF-04447943) that was first tested for Alzheimer's disease, though eventually abandoned for this use. Between the two reported clinical trials, over 100 subjects received this drug, and it was found to be well tolerated with no serious adverse side effects. A different PDE9 inhibitor is now being tested for human heart failure.

Researchers kept mice on a high-fat diet that led to doubling their body weight, high blood lipids and diabetes after four months.

A group of female mice had their ovaries surgically removed, and most of the mice also had a pressure stress applied to the heart to better mimic cardiometabolic syndrome. The mice were then assigned to receive either the PDE9 inhibitor or a placebo by mouth over the next six to eight weeks.

In female mice without their ovaries (a model of postmenopause), the difference in median percent weight change between the drug and placebo groups was -27.5%, and in males it was -19.5%. Lean body mass was not altered in either group, nor was daily food consumption or physical activity.

The PDE9 inhibitor lowered blood cholesterol and triglycerides, and reduced fat in the liver to levels found in mice fed a normal diet.

The heart also improved with PDE9 inhibition, with ejection fraction relatively higher by 7%-15% and heart mass rising 70% less compared with the placebo. An increase in heart mass is evidence of abnormal heart stress. However, having this lowered by the inhibitor indicates stress on the heart was reduced.

The investigators found PDE9 inhibition produces these effects by activating PPARa. By stimulating PPARa, levels of genes for proteins that control fat uptake into cells and their use as fuel are broadly increased.

When PPARa was blocked in cells or the whole animal, the effects from PDE9 inhibition on obesity and fat-burning were also lost.

They found estrogen normally plays this role of PPARa on fat regulation in females, but when its levels fall like they do after menopause, PPARa becomes more important to regulate fat and so PDE9 inhibition has a greater effect.

"The finding that the experimental drug did not benefit female mice that had their ovaries shows that these sex hormones, particularly estrogen, had already achieved what inhibiting PDE9 does to stimulate fat-burning," notes Sumita Mishra, the research associate who performed much of the work.

"Menopause reduces sex hormone levels, and their control over fat metabolism then shifts to the protein regulated by PDE9, so the drug treatment is now effective."

Kass notes that if his lab's findings in mice apply to people, someone weighing 250 pounds could lose about 50 pounds with an oral PDE9 inhibitor without changing eating or exercise habits.

"I'm not suggesting to be a couch potato and take a pill, but I suspect that combined with diet and exercise, the effects from PDE9 inhibition may be even greater," says Kass. The next step would be testing in humans to see if PDE9 inhibitors produce similar effects in men and postmenopausal women.

"PDE9 inhibitors are already being studied in humans, so a clinical obesity study should not be that far away," Kass says.



Source: Medindia