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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.

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