Campolo Federica, Giampaoli Ottavia, Barbagallo Federica, Palmisano Biagio, Di Maio Anna, Sciarra Francesca, Rizzo Flavio, Monti Serena, Albanese Sandra, Cardarelli Silvia, Assenza Maria Rita, Poggiogalle Eleonora, Patriarca Adriano, Sciubba Fabio, Filippini Antonio, Lenzi Andrea, Gianfrilli Daniele, Giorgi Mauro, Dolci Susanna, Naro Fabio, Sampaolesi Maurilio, Riminucci Mara, Miccheli Alfredo, Tessarollo Lino, Venneri Mary Anna, Isidori Andrea M
Department of Experimental Medicine, Sapienza University of Rome, Rome, 00161, Italy; Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Histology and Medical Embryology, Sapienza University of Rome, Rome, 00161, Italy; Saint Camillus International, University of Health Sciences, Rome, 00133, Italy.
NMR-Based Metabolomics Laboratory (NMLab), Sapienza University of Rome, Rome, 00185, Italy; Department of Environmental Biology, Sapienza University of Rome, Rome, 00185, Italy.
Mol Metab. 2025 Nov;101:102243. doi: 10.1016/j.molmet.2025.102243. Epub 2025 Sep 3.
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.
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.
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.
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.
环核苷酸是脂肪生成和适应性产热的核心调节因子，其细胞内浓度受磷酸二酯酶（PDEs）严格控制。其中，5型磷酸二酯酶（PDE5A）调节脂肪细胞中环磷酸鸟苷（cGMP）的周转。尽管已对PDE5A抑制在糖尿病中的作用进行了探索，但其在全身代谢中的作用仍不清楚。
我们使用不同的Pde5a基因敲除小鼠模型来研究PDE5A缺乏对脂肪组织生物学和全身能量稳态的影响。在正常饮食和高脂饮食条件下进行表型、组织学和代谢评估，重点关注产热激活、肝脏脂质积累和葡萄糖代谢。
Pde5a缺失导致棕色脂肪组织强烈激活和白色脂肪库中度棕色化，同时肝脏脂质含量降低。在高脂饮食挑战下，Pde5a缺陷小鼠表现出对肥胖的抵抗力、改善的葡萄糖处理能力和增强的产热能力。从机制上讲，这些保护作用源于Pde5a的早期发育敲低，其通过激活cAMP-蛋白激酶A（PKA）信号通路诱导代谢重编程。cGMP和cAMP信号级联的汇聚协调了全身代谢适应。
我们的研究确定PDE5A是一种先前未被认识的产热和能量平衡调节因子。因此，靶向PDE5A可能代表一种有前景的辅助治疗方法，用于治疗代谢紊乱。
