Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9
Year: 2021
Type: article
Abstract: Obesity is a central component to cardiometabolic diseases, predisposing patients to both heart failure and diabetes. As therapeutics targeting caloric intake have limited long-term efficacy, greater interest has been on increasing thermogenic energy expenditure. Cyclic nucleotides, cAMP and cGMP, are important second messengers that are critical for the regulation of adaptive thermogenesis. These are regulated not only by their synthesis but also by their degradation. Pharmacological inhibitors of the cGMP-specific phosphodiesterase 9 (PDE9) increased PKG signaling and UCP1 expression in adipocytes. To elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo , mice carrying a targeted disruption of the PDE9 gene, Pde9a , were fed a nutrient matched high-fat diet (HFD) or low-fat diet (LFD). Pde9a -/- mice were resistant to obesity induced by a HFD. Pde9a -/- mice exhibited a global increase in energy expenditure while the brown adipose tissue had elevated expression of Ucp1 and other thermogenic genes. The reduced adiposity of HFD-fed Pde9a -/- mice was associated with improvements in glucose handling and hepatic steatosis. These findings support the conclusion that PDE9 is a critical regulator of energy metabolism and suggest that inhibiting this enzyme may be an important avenue to explore for combating metabolic disease.
Source: Diabetes
DOI: 10.2337/db21-0100
Authors: Ryan P. Ceddia, Dianxin Liu, Fubiao Shi, Mark K. Crowder, Sumita Mishra, David A. Kass, Sheila Collins
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Funders: American Diabetes Association, American Heart Association, Vanderbilt University, Johns Hopkins University, National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources
Awards: G1002678292, G117257630, G1221739687, G1280513408, G1388609297, G1805704937, G1965827270, G2006259475, Leica Bond RX, G3152736877, Vanderbilt Mouse Metabolic Phenotyping Center, Leveraging Protein Kinase G-1 Nanodomain Control and Molecular Targeting to Enhance its Therapeutic Use Against Myocardial Disease, G4182348267, G4424950377, G4513176822, Natriuretic peptide receptors, adipose browning and energy expenditure, Gas Chromotograph- Triple Quadrupole Tandem Mass Spectrometer (GC-QqQ), G5436572433, G5853943267, Comprehensive Laboratory Animal Measurement System (CLAMS), G6623812506, G81352558, G8366546091, The role of phosphodiesterase 9 in the regulation of adipocyte thermogenesis and obesity-related diseases, Female sex-hormones and cyclic GMP-PKG Modulation of Cardiac Disease and Metabolism, G9000052735, G9000081609, G9000089795, G9000130502, Cancer Center Support Grant, Vanderbilt Diabetes Research Center
OpenAlex ID: W3204739474