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

Abstract

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.

• Authors: Zhuoran Wang, Yaru Liang, Lu Zhang, Nannan Zhang, Qingfei Liu, Zhao Wang
• Journal: Aging (Aging (Albany NY)) Vol. 10 Issue 9 Pg. 2394-2406 (09 18 2018) ISSN: 1945-4589 [Electronic] United States
• PMID: 30227388 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Phosphodiesterase 4 Inhibitors
• Cyclic AMP
• Sirt6 protein, mouse
• Calcium-Calmodulin-Dependent Protein Kinase Kinase
• AMP-Activated Protein Kinases
• Sirtuins
• Rolipram

Topics

• 3T3-L1 Cells
• AMP-Activated Protein Kinases (physiology)
• Adipose Tissue (metabolism)
• Aging (metabolism)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Kinase (physiology)
• Cyclic AMP (analysis)
• Male
• Metabolic Diseases (drug therapy, metabolism)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• Phosphodiesterase 4 Inhibitors (pharmacology, therapeutic use)
• Rolipram (pharmacology)
• Signal Transduction (drug effects)
• Sirtuins (analysis, physiology)