PhD Scientific Days 2025

Poster Session I. - F: Pharmaceutical Sciences and Health Technologies

Resveratrol and Its Derivatives Reduce Adipogenesis in Mouse Embryonic Fibroblasts - Study on Mechanism of Action

Name of the presenter

Sikur Noémi Blanka

Institute/workplace of the presenter

Semmelweis University Department of Pharmacodynamics

Authors

Noémi Sikur¹, Alexandra Paszternak¹, Kamilla Varga¹, Tamás Tábi¹

1: Semmelweis University Department of Pharmacodynamics

Text of the abstract

Introduction: Resveratrol, a dietary polyphenolic compound, has been a widely researched antioxidant molecule. Recent studies also reported, that it might have beneficial effects in obesity-related complications, however its mechanism of action and exact molecular targets are yet unclear. Its poor bioavailability hinders its therapeutic use, which could be addressed by testing structurally modified analogues.
Aim: In our present study we aimed at observing the metabolic effects of resveratrol and its analogues on adipogenesis in vitro.
Method: Mouse embryonic fibroblasts were differentiated into adipocytes over 21 days when cells were also treated with resveratrol or one of its derivatives (oxyresveratrol, mono- or trimethylated resveratrol). To investigate molecular pathways, specific inhibitors (PI3K: Wortmannin, SIRT1: EX-527, p38: SB202190 and PGC-1α: SR18292, autophagy: chloroquin, ERK: PD98059, JNK: SP600125) were applied simultaniously. Intracellular lipid accumulation was assessed by Oil Red O staining. Glucose uptake was assessed by 2-NBDG, a fluorescent glucose analogue. Mitochondrial activity was estimated by resazurin reduction.
Results: Although each analogue significantly reduced intracellular lipid content, oxyresveratrol was the most potent (IC50=4.2 μM), while the lowest potency was observed with trimethylated resveratrol (IC50=27.4 μM). Inhibition of PI3K attenuated differentiation, with p38, ERK inhibitors the adipogenesis reducing effect remained, however with SIRT1, PGC-1α, autophagy and JNK inhibition the lipid content decreasing effect of the derivatives disappeared. Enhanced insulin stimulated glucose uptake was normalised by every analogue with similar efficiency. In adipocytes increased mitochondrial activity was observed, which was restored by methylated resveratrols, while oxyresveratrol had minimal if any effect in this case.
Conclusions: Based on our results we concluded, that modifications like oxidation and methylation may affect the mechanism of action, as oxyresveratrol had a robust lipid reducing effect, while methylated analogues had stronger effect on mitochondrial activity and autophagy. Resveratrol and its analogues might mimic caloric restriction through various molecular targets like SIRT1, PGC1α, and JNK, making them possible drug candidates to treat obesity-related diseases.
Funding: EKÖP-2024-259