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Some effects of resveratrol and SRT1720 on PKA‐signaling and AMP‐kinase in adipocytes may be related to inhibition of Cyclic Nucleotide Phosphodiesterases (PDEs)
Author(s) -
Khan Faiyaz,
Park SungJun,
Chung Jay,
Manganiello Vincent
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.914.4
Subject(s) - rolipram , ampk , resveratrol , phosphorylation , chemistry , creb , protein kinase a , phosphodiesterase , kinase , amp activated protein kinase , biochemistry , microbiology and biotechnology , pharmacology , biology , enzyme , transcription factor , gene
In animal models, caloric restriction (CR) decreases the incidence of age‐associated disorders such as cardiovascular disease, diabetes, and cancer. SIRT1 activators, i.e., resveratrol (RES) and SRT1720 (SRT), mimic effects of CR in lower organisms and mice. In 3T3‐L1 adipocytes, resveratrol and SRT inhibited PDE activities in membrane (IC50, ~40 and 7.5 uM respectively), and cytosol (IC50, ~90 and 10 uM, respectively). Cilostamide (10 uM), RES (12.5 uM), SRT (2 uM), and rolipram (30 uM), increased phosphorylation of Ser133‐CREB, Ser431‐LKB, Thr172‐AMPK, Ser79‐ACC as well as other unidentified PKA substrates. Rp‐8‐Br‐cAMPs, PKA inhibitor, blocked phosphorylation of these signaling molecules by cilostamide and rolipram. Rolipram had a relatively stronger effect on phosphorylation of PKA substrates and CREB than cilostamide, RES and SRT, but had smaller effect on the phosphorylation of LKB, AMPK, and ACC, suggesting the presence of a distinct cAMP pool involved in activation of AMPK. In adipocytes incubated for 90 min with CL‐316243 (B3‐agonist), 10 uM RES or 2 uM SRT increased phosphorylation of Ser563‐HSL, resulting in a significant increase in lipolysis (glycerol release). These and other results provide evidence that at least some effects of resveratrol and SRT‐1720 may be related to their inhibition of PDEs and, thereby, alteration of intracellular cAMP concentrations.