Johns Hopkins Medicine researchers have discovered how a drug developed for the first time to treat Alzheimer’s disease, schizophrenia and sickle cell anemia, is able to reduce theobesity and fatty liver in mice, with no changes in diet and daily activities. It is a inhibitor chemist ofPDE9 enzyme, whose efficacy has been demonstrated in both male and female rodents. The latter had their ovaries removed, resulting in the induction of a menopausal state.
It has long been known that postmenopausal women are at increased risk of suffering from obesity and developing cardiovascular and metabolic diseases. The studio, published on “Journal of Clinical Investigation”, follows the analysis of the same team that in 2015 showed that the PDE9 enzyme is present in the heart and contributes to the onset of heart diseases triggered by hypertension.
Blocking PDE9 increases the amount of a small molecule known as cyclic GMP which in turn controls many aspects of cellular function throughout the body. This enzyme is also a “cousin” of another protein called PDE5 which keeps an eye on cyclic GMP and is blocked by drugs such as Viagra. Based on these results, the scientists hypothesized that PDE9 inhibition was able to improve cardiometabolic syndrome, which is a set of common conditions including: obesity, hypertension, high blood sugar, hypercholesterolemia and excess triglycerides. Cardiometabolic syndrome is considered a major risk factor for stroke, heart disease, cancer, type 2 diabetes and Covid.
A PDE9 inhibitor manufactured by Pfizer Inc. previously tested for Alzheimer’s and then abandoned for such use was used for the current study. Over 100 subjects received this molecule, which was well tolerated and did not elicit serious adverse reactions. In order to test the effects of a PDE9 inhibitor on obesity and cardiometabolic syndrome, the team administered a diet rich in fat which doubled their body weight, blood lipids and diabetes after four months. A group of female rodents were surgically removed ovaries and most animals had pressure stress applied to the heart to mimic the metabolic syndrome. Finally, some of them received the PDE9 inhibitor and others a placebo over the next 6-8 weeks.
In female rodents without ovaries, the difference in median percent change in weight between the drug and placebo groups was -27.5%; in males it was, on the other hand, -19.5%. Lean mass was not altered in either group, nor was daily food consumption or physical activity altered. The PDE9 inhibitor lowered blood cholesterol and triglycerides and reduced fat in the liver. Cardiac function also improved, with relatively higher ejection fraction 7-15% and hypertrophy 70% less than placebo. Inhibition of PDE9 produces these effects by activating a regulator main of metabolism fat known as PPARa. By stimulating the latter, the levels of genes for proteins that control the absorption of fat into cells and their use as fuel are greatly increased.
When PPARa was blocked in cells, the effects of PDE9 inhibition on obesity and fat burning were also lost. It has been found that normally theestrogen plays this role of PPRa on fat regulation in females. However when its levels decrease (for example after menopause), PPRa becomes more important for regulating fat and therefore the inhibition of PDE9 has a greater effect. According to scholars, if the results of the analysis applied to people, they could lose weight with oral intake of a PDE9 inhibitor without changing eating or exercise habits. Further investigation is needed.