By Wendy Bindeman
A trans-institutional team that includes Professor of Medicine and Molecular Physiology and Biophysics Sheila Collins, first author and Collins lab postdoc Ryan Ceddia, and Johns Hopkins collaborators Dr. David Kass and Sumita Mishra recently published a study showing that mice lacking an enzyme called phosphodiesterase-9 or PDE9 are resistant to diet-induced obesity due to increased energy expenditure and cold-induced “browning” of fat tissue. Their findings were published online in October 2021 in the journal Diabetes.
We sat down with Ceddia to learn more about this exciting new research.
What problem does your research address?
Obesity is a serious health concern that is increasingly prevalent in the U.S. and worldwide. It is associated with a plethora of diseases including diabetes, cardiovascular disease, and certain cancers. Current anti-obesity therapeutics act as appetite suppressants or block fat absorption from the gut, but these have undesirable side effects or eventually lose efficacy. A yet-untapped approach to target obesity is to boost energy expenditure by increasing energy-consuming futile metabolic cycles and uncoupled respiration (a process that describes proton transport into the mitochondria without the expected production of energy). These futile cycles exist mainly to generate heat for the body, since, we must remember, in the cave days there were no houses and clothing was rudimentary. So, it was necessary to burn calories in order to maintain one’s body temperature. In these studies, we used a global gene deletion of PDE9 to show that mice lacking the enzyme have a small increase in energy expenditure, which over time leads to a significant reduction in obesity.
What was unique about your approach to the research?
Brown adipose tissue is a special kind of fat cell that contains a high number of mitochondria, which causes their brownish color. Mitochondria in brown fat also contain a unique “uncoupling protein” called UCP1, which creates one of these futile cycles that generate heat. Uncoupled respiration and thermogenic, or heat-producing, activity are increased in fat cells via a process called “browning” of energy-storing white adipose tissue.
Fat tissue “browning” occurs when genes for mitochondria and UCP1 are expressed in white fat tissue, making it more similar to brown fat. It is induced in part by increasing the intracellular concentration of the molecules cAMP and cGMP, and in this study we examined the effect of preventing cGMP degradation by PDE9. Phosphodiesterases are enzymes that degrade cAMP and cGMP, but PDE9 is unique in that it is one of the two phosphodiesterases in fat cells that only degrade cGMP. Using mice lacking PDE9, we examined the effects of PDE9 loss on weight gain, energy expenditure, and glucose homeostasis.
What were your findings?
We found that mice that lack PDE9 gain less weight than wild-type mice when challenged with a high-fat diet due to a global increase in energy expenditure. This increase in energy expenditure at any given time was small; however, over the extended course of the study—16 weeks during which the mice were fed a high-fat diet—it led to a significant reduction in body weight and fat mass.
We observed significant changes in the fat tissue of these PDE9 knockout mice that contributed to the increase in energy expenditure. The brown fat tissue from the PDE9 knockout mice had increased respiratory capacity (in other words, a higher metabolism), and we observed increased expression of genes associated with thermogenic activity in both white and brown fat tissue. Improvements in the ability to regulate blood glucose were associated with a reduction in body weight. In addition, the livers of the PDE9 knockout mice were resistant to both fat accumulation and liver damage induced by the high-fat diet.
What do you hope will be achieved with the research results in the short and long terms? What are the societal/environmental/economic benefits of this research?
These studies highlight the importance of cGMP-PKG signaling in fat tissue thermogenesis (PKG is an enzyme that is one of the targets of cGMP), and suggest that PDE9 may be a good target for anti-obesity therapeutics. Several pharmaceutical companies are already developing PDE9 inhibitors for conditions such as Alzheimer’s disease, sickle cell disease, and schizophrenia. As they have been found to be safe for patients in clinical trials, we hope these findings will encourage them to consider their potential for treating obesity.
Furthermore, our Johns Hopkins collaborators Dr. David Kass and Sumita Mishra have demonstrated, with our lab’s help, that PDE9 inhibitors have a beneficial effect on cardiovascular function in mice, results that they published in a companion paper in the Journal of Clinical Investigation. As obesity and cardiovascular disease often present simultaneously in patients, the beneficial effects of PDE9 inhibition on both obesity and heart function suggest that PDE9 inhibitors may also be useful for the treatment of what is called “cardiometabolic syndrome.”
Where is this research taking you next?
An interesting finding of these studies was that mice lacking PDE9 are more responsive to cold-induced fat tissue browning and that a reduction in Pde9 gene expression that occurs when someone is exposed to cold temperatures may be important for inducing cold-mediated thermogenesis in brown fat. This was unexpected as the classical model for cold-induced fat tissue browning relies entirely upon cAMP, but because PDE9 is highly selective for cGMP, these findings suggest a novel role for cGMP in this process. We plan to launch an investigation into the classical cold-induced fat tissue browning program to investigate the contribution of PDE9 and other cGMP-associated signaling molecules.
Funding
This work was supported by National Institutes of Health, the American Heart Association, and the American Diabetes Association, and additional Vanderbilt institutional funds.
Go Deeper
The article “Increased Energy Expenditure and Protection from Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9” was published online in the journal Diabetes in October 2021.