Phosphodiesterase 4 inhibitor activates AMPK-SIRT6 pathway to prevent aging-related adipose deposition induced by metabolic disorder

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.