Journal
AGING-US
Volume 10, Issue 9, Pages 2394-2406Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.101559
Keywords
rolipram; aging; adipose deposition; AMPK; SIRT6
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Funding
- National Key R&D Program of China [2018YFD0400204]
- Key International S&T Cooperation Program of China [2016YFE113700]
- European Union's Horizon 2020 Research and Innovation Program [633589]
- National Natural Science Foundation of China [81471396]
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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-kappa B 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.
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