Pde5a deficiency prevents diet-induced obesity via adipose cAMP-PKA activation enhancing fat browning

Objective: Cyclic nucleotides are central regulators of adipogenesis and adaptive thermogenesis, with their intracellular concentrations tightly controlled by phosphodiesterases (PDEs). Among them, phosphodiesterase type 5 (PDE5A) regulates cyclic guanosine monophosphate (cGMP) turnover in adipocytes. Although PDE5A inhibition has been explored in diabetes, its role in systemic metabolism remains poorly defined. Methods: We employed different Pde5a knockout mouse models to investigate the impact of PDE5A deficiency on adipose tissue biology and whole-body energy homeostasis. Phenotypic, histological, and metabolic assessments were performed under chow and high-fat diet conditions, with a focus on thermogenic activation, hepatic lipid accumulation, and glucose metabolism. Results: Loss of Pde5a resulted in robust activation of brown adipose tissue and moderate browning of white adipose depots, accompanied by a reduction in hepatic lipid content. Upon high-fat diet challenge, Pde5a-deficient mice exhibited resistance to obesity, improved glucose handling, and enhanced thermogenic capacity. Mechanistically, these protective effects originated from early developmental knockdown of Pde5a, which induced metabolic reprogramming via activation of the cAMP—protein kinase A (PKA) signaling pathway. The convergence of cGMP and cAMP signaling cascades orchestrated systemic metabolic adaptations. Conclusions: Our study identifies PDE5A as a previously unrecognized regulator of thermogenesis and energy balance. Targeting PDE5A may therefore represent a promising adjuvant therapeutic approach for the treatment of metabolic disorders.