Research Paper Volume 10, Issue 9 pp 2394—2406
Phosphodiesterase 4 inhibitor activates AMPK-SIRT6 pathway to prevent aging-related adipose deposition induced by metabolic disorder
- 1 MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, P.R. China
received: June 14, 2018 ; accepted: September 12, 2018 ; published: September 18, 2018 ;https://doi.org/10.18632/aging.101559
How to Cite
Copyright: Wang et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Rolipram is a selective phosphodiesterase 4 (PDE4) inhibitor that exerts a variety of effects, including anti-inflammatory, immunosuppressive, and anti-tumor effects. The aim of this study was to investigate the effect of rolipram on metabolic disorder and its underlying mechanisms. Metabolic disorder was induced in 8-week-old wild type BABL/c mice by administration of D-galactose for 4 weeks. Simultaneously the mice were administered vehicle or rolipram. Alternatively, beginning at 3 or 21 months, the mice were administered db-cAMP for 3 months, with or without a high-fat-diet (HFD) to induce metabolic disorder. In both models, better metabolic function was observed in rolipram-treated mice. Rolipram reduced adipose deposition and inflammation and reserved metabolic disorder. Treatment with rolipram increased the AMPK phosphorylation and SIRT6 levels in the liver and kidney while reducing NF-κB acetylation. In vitro, these effects were blocked by suppression of SIRT6 expression using specific siRNA. Increased cAMP levels reduced excessive adipose deposition, and improved adipose distribution in presenile mice. These findings provide a promising strategy for the treatment of aging-related metabolic dysfunctions and suggest that selective PDE4 inhibitors may be useful agents for the treatment of aging-related metabolic diseases.