Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9

Abstract

Cyclic nucleotides cAMP and cGMP are important second messengers for the regulation of adaptive thermogenesis. Their levels are controlled not only by their synthesis, but also their degradation. Since pharmacological inhibitors of cGMP-specific phosphodiesterase 9 (PDE9) can increase cGMP-dependent protein kinase signaling and uncoupling protein 1 expression in adipocytes, we sought to elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo. Mice with targeted disruption of the PDE9 gene, Pde9a, were fed nutrient-matched high-fat (HFD) or low-fat diets. Pde9a−/− mice were resistant to HFD-induced obesity, exhibiting a global increase in energy expenditure, while brown adipose tissue (AT) had increased respiratory capacity and elevated expression of Ucp1 and other thermogenic genes. Reduced adiposity of HFD-fed Pde9a−/− mice was associated with improvements in glucose handling and hepatic steatosis. Cold exposure or treatment with β-adrenergic receptor agonists markedly decreased Pde9a expression in brown AT and cultured brown adipocytes, while Pde9a−/− mice exhibited a greater increase in AT browning, together suggesting that the PDE9-cGMP pathway augments classical cold-induced β-adrenergic/cAMP AT browning and energy expenditure. These findings suggest PDE9 is a previously unrecognized regulator of energy metabolism and that its inhibition may be a valuable avenue to explore for combating metabolic disease.

Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies

“…A more recent study showed that overexpression of PDE4D in the liver led to the development of NAFLD and hypertension in mice, which was attenuated by PDE4 inhibitor treatment [60]. Beyond PDE4, recent papers have shown a role of PDE9 and 10 in liver and lung fibrosis as well as diet-induced obesity [61][62][63][64]. Our data show a significant upregulation of PDE9A and 10A in the livers of AH patients (Figure 5).…”

Protein kinase D1 (Prkd1) deletion in brown adipose tissue leads to altered myogenic gene expression after cold exposure, while thermogenesis remains intact

“…On day 5, iBAT and iWAT were dissected and immediately placed in Trizol (ThermoFisher). Similar CL316,243 treatments in mice have been performed in the lab (Ceddia et al, 2021; Liu et al, 2016b).…”

Phosphodiesterase 3 inhibitors boost bone outgrowth

“…Based on their biological features, PDE1B and PDE2A are unlikely to contribute to establishing the basal cGMP concentration under resting conditions. Pde5a- knockout mice exhibit small body sizes (Data ref: International Mouse Phenotyping Consortium MGI: 2651499, 2011), and Pde9a -knockout mice have normal body sizes (Ceddia et al , 2021), suggesting that inhibitors of PDE5A and PDE9A are unlikely to stimulate bone growth. Pde6g -knockout mice develop retinitis pigmentosa blindness but have normal body sizes (Tsang et al , 1996).…”