A relative of Viagra burns fat
Researchers from the Johns Hopkins University School of Medicine have shown that a drug developed for the treatment of Alzheimer's disease, schizophrenia and sickle cell anemia fights obesity and fatty liver degeneration in mice and improves cardiac function in the absence of changes in diet and maintaining the same activity. An inhibitor of the enzyme phosphodiesterase 9 (PDE9) stimulated cells to burn more fat in male mice, as well as in females who had their ovaries removed in order to lower the level of female sex hormones and thus simulate menopause. It is known that women in the postmenopausal period are at increased risk of obesity in the abdominal area, as well as cardiovascular and metabolic diseases. Inhibition of PDE9 did not cause changes in fat metabolism in female mice that had ovaries, so the status of female sex hormones was important in the study.
A research team led by David Kass in 2015 showed for the first time that the enzyme PDE9 accumulates in the heart and contributes to the development of cardiovascular diseases associated with high blood pressure. Blocking PDE9 increases the amount of cyclic guanosine monophosphate (cGMP), which in turn controls many aspects of cell functions throughout the body. PDE9 is a cousin of the enzyme PDE5, which also controls cGMP and is blocked by the well-known drug Viagra. PDE9 inhibitors do not have a name yet, as they are under testing.
Based on the results obtained in 2015, the researchers suggested that inhibition of PDE9 will help fight metabolic syndrome – a set of pathological conditions including hypertension, high blood sugar, cholesterol and triglycerides and excess adipose tissue in the body, especially in the waist area. Medical experts consider metabolic syndrome to be a pandemic and a major risk factor for cardiovascular diseases, stroke, type 2 diabetes, cancer and COVID-19.
Despite the experimental status of PDE9 inhibitors, they have been refined by several pharmaceutical companies and tested in humans for the treatment of diseases such as Alzheimer's disease and sickle cell anemia. In a new study on mice, a Pfizer PDE9 inhibitor was used, which was originally created for the treatment of Alzheimer's disease. More than 100 volunteers participated in two published clinical trials of this drug, and it was found that it is well tolerated and has no serious side effects. Another PDE9 inhibitor is currently being investigated for the treatment of heart failure.
To assess the effect of the PDE9 inhibitor on obesity and cardiometabolic syndrome, the researchers gave mice a high-fat diet, which led to a doubling of their body weight, an increase in blood lipids and the development of diabetes after four months. A group of females had their ovaries surgically removed, and most mice also had their hearts squeezed in order to more accurately simulate cardiometabolic syndrome. The mice were then given either a PDE9 inhibitor or a placebo orally for the next six to eight weeks.
In female mice with removed ovaries (postmenopausal model), the difference in the average percentage change in weight between the drug and placebo groups was 27.5%, and in males – 19.5%. The proportion of muscle mass did not change in any of the groups, as well as the daily diet or physical activity. The PDE9 inhibitor lowered the level of cholesterol and triglycerides in the blood, as well as the content of fatty tissue in the liver to levels found in mice receiving a normal diet. The heart function was normalized due to PDE9 inhibition: the ejection fraction (the percentage of blood leaving the heart with each contraction) became 7-15% higher, and the heart mass (hypertrophy) was added 70% less compared to placebo. An increase in heart mass indicates a stress load, and the PDE9 inhibitor reduced it.
The researchers found that inhibition of PDE9 leads to activation of the main regulator of fat metabolism – the peroxisome proliferator-activated receptor-α (PPARa). Stimulation of PPARa increases the activity of genes that control the absorption of fat by cells and its use as fuel. Blocking PPARa in cells led to a loss of the effectiveness of PDE9 inhibitors against obesity. They found that estrogen usually performs the function of PPARa in fat metabolism in women, but when its level drops, as it does after menopause, PPARa becomes more important, and therefore blocking PDE9 has a greater effect.
The absence of a PDE9 inhibitor effect in female mice with functioning ovaries suggests that female sex hormones, especially estrogen, stimulate fat burning themselves. After menopause, the level of sex hormones decreases, and their control over fat metabolism then passes to a protein regulated by PDE9, so drug treatment becomes effective.
According to the US Centers for Disease Control and Prevention, more than 40% of people living in the US are obese. Among menopausal women, this proportion is 43%. If the results of the study on mice are translated into human parameters, then at a weight of 100 kg, the loss against the background of oral administration of the PDE9 inhibitor without changing eating habits and physical activity can be about 20 kg.
The next step is to evaluate the effectiveness of PDE9 inhibitors in postmenopausal women and men. These drugs are already being tested on humans, so a clinical study of obesity can be expected in the near future.
Article by S.Mishra et al. Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice is published in the Journal of Clinical Investigation.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru Based on Johns Hopkins Medicine: A Cousin of Viagra Reduces Obesity by Stimulating Cells to Burn Fat, Study Shows.