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Viagra analog found to reduce obesity without caloric intake reduction

The Johns Hopkins research team found that the drug, a “cousin” to Viagra, reduced the groups median body weight by -27.5% in female mice and -19.5% in male mice.

Obesity has recently become one of the most pressing worldwide health issues. Obesity rates tripled globally between 1975 and 2016, owing largely to a high-calorie diet and a sedentary lifestyle. According to a World Health Organization study from 2016, the prevalence of being overweight was similar among men (39%) and women (40%).

Researchers at Johns Hopkins Medicine have discovered that a medication originally intended to treat Alzheimer’s disease, schizophrenia, and sickle cell disease decreases obesity and fatty liver in mice, as well as improving their cardiac function, without requiring them to modify their diet or daily exercise.

These findings, which were published in the Journal of Clinical Investigation on October 7th, show that a pharmacological inhibitor of the enzyme PDE9 encourages cells to burn more fat. This happened in both male and female mice that had their sex hormones suppressed by removing their ovaries, simulating menopause. Obesity around the waist, as well as cardiovascular disease and metabolic syndrome, are all recognized to be elevated risks for postmenopausal women.

Female mice with their ovaries removed did not show similar alterations when PDE9 was inhibited, indicating that female sex hormone status was significant in the study.

File:Viagra Tablette.jpg - Wikimedia Commons
Sildenafil, commonly known as Viagra, is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.

“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,” stated author David Kass, M.D., 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.”

Blocking PDE9 raises the quantity of cyclic GMP, a tiny molecule that regulates many aspects of cell activity throughout the body. PDE9 is an enzyme relative of PDE5, another protein that regulates cyclic GMP and is inhibited by medicines like Viagra. Because PDE9 inhibitors are still under development, there is no name for them yet.

The researchers fed mice a high-fat diet for four months to see how a PDE9 inhibitor affected obesity and cardiometabolic syndrome. After four months, the mice had doubled their body weight, elevated blood lipids, and diabetes. To better simulate cardiometabolic syndrome, a group of female mice had their ovaries surgically removed, and majority of the animals also had a pressure stress applied to their hearts. During the next six to eight weeks, the mice were given either the PDE9 inhibitor or a placebo by mouth.

The difference in median percent weight change between the medication and placebo groups was -27.5% in female mice lacking their ovaries (a model of postmenopause), and -19.5% in male mice. In neither group, lean body mass, daily food consumption, or physical activity were altered.
The PDE9 inhibitor decreased blood cholesterol and triglycerides, as well as liver fat, to levels seen in mice fed a regular diet. The heart also benefited from PDE9 inhibition, with ejection fraction (the proportion of blood leaving the heart each time it contracts) rising 7%-15% and heart mass (hypertrophy) growing 70% less than with the placebo.

“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,” co-author Sumita Mishra stated. “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.”

Dr. David Kass concluded, “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…PDE9 inhibitors are already being studied in humans, so a clinical obesity study should not be that far away.”


The study was published in The Journal of Clinical Investigation, on October 7th, 2021.

Abstract. Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) in both ovariectomized female or male mice suppresses pre-established severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure-load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat, stimulating mitochondrial activity in brown and white fat, and improving CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis and mitochondrial respiration in adipocytes and myocytes coupled to PPARα-dependent gene regulation. PPARα upregulation was required to achieve the lipolytic, anti-obesity, and metabolic effects of PDE9-I. All these PDE9-I induced changes were not observed in obese/CMS non-ovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was re-oriented away from fat-metabolism regulating genes when stimulated in the presence of co-activated estrogen receptor-alpha, and this may underly the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Mishra S, Sadagopan N, Dunkerly-Eyring B, Rodriguez S, Sarver DC, Ceddia RP, Murphy SA, Knutsdottir H, Jani VP, Ashok D, Oeing CU, O’Rourke B, Gangoiti JA, Sears DD, Wong GW, Collins S, Kass D. Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice. J Clin Invest. 2021 Oct 7:e148798. doi: 10.1172/JCI148798. Epub ahead of print. PMID: 34618683.

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