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Resveratrol and Its Derivatives Diminish Lipid Accumulation in Adipocytes In Vitro-Mechanism of Action and
Noémi Sikur1,2, Csenge Böröczky1,2, Alexandra Paszternák1,2
1Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad Tér, H-1089 Budapest, Hungary.
Background And Objectives:
Expansion of white adipose tissue causes systemic inflammation and increased risk of metabolic diseases due to its endocrine function. Resveratrol was suggested to be able to prevent obesity-related disorders by mimicking caloric restriction; however, its structure-activity relationships and molecular targets are still unknown. We aimed to compare the effects of resveratrol and its analogues on adipocyte metabolism and lipid accumulation in vitro.
Methods:
Mouse embryonic fibroblasts were differentiated to adipocytes in the absence or presence of resveratrol or its derivatives (oxyresveratrol, monomethylated resveratrol, or trimethylated resveratrol). Intracellular lipid content was assessed by Oil Red O staining. Glucose uptake and its response to insulin were estimated by 2-NBDG, and mitochondrial activity was assayed via resazurin reduction. Involvement of potential molecular pathways was investigated by concurrent treatment with their inhibitors.
Results:
Although lipid accumulation was significantly reduced by all analogues without altering protein content, oxyresveratrol was the most potent (IC50 = 4.2 μM), while the lowest potency was observed with trimethylated resveratrol (IC50 = 27.4 μM). Increased insulin-stimulated glucose uptake was restored by each analogue with comparable efficiency. The enhanced mitochondrial activity was normalized by resveratrol and its methylated derivatives, while oxyresveratrol had a minor impact on it. Among the examined pathways, inhibition of SIRT1, PGC-1α, and JNK diminished the lipid-reducing effect of the compounds. Autophagy appeared to play a key role in the effect of all compounds but oxyresveratrol.
Conclusions:
Resveratrol and its analogues can mimic caloric restriction with complex mechanisms, including activation of SIRT1, PGC-1α, and JNK, making them possible drug candidates to treat obesity-related diseases.
Insights
Resveratrol and its analogues reduce fat accumulation in adipocytes by mimicking caloric restriction. These compounds activate pathways like SIRT1, PGC-1α, and JNK, showing potential for treating obesity-related diseases.
Area of Science:
- Metabolic disease research
- Adipocyte biology
- Pharmacology of natural compounds
Background:
- White adipose tissue expansion drives systemic inflammation and metabolic disease risk.
- Resveratrol is proposed to combat obesity by mimicking caloric restriction.
- The precise mechanisms and molecular targets of resveratrol in this context remain unclear.
Purpose of the Study:
- To investigate the effects of resveratrol and its analogues on adipocyte metabolism and lipid accumulation.
- To compare the potency and efficacy of different resveratrol derivatives in vitro.
- To elucidate the molecular pathways involved in the action of resveratrol and its analogues.
Main Methods:
- Mouse embryonic fibroblasts were differentiated into adipocytes.
- Lipid accumulation was quantified using Oil Red O staining.
- Glucose uptake, insulin response, and mitochondrial activity were assessed.
- The involvement of specific molecular pathways (SIRT1, PGC-1α, JNK, autophagy) was examined using inhibitors.
Main Results:
- All resveratrol analogues significantly reduced lipid accumulation in adipocytes.
- Oxyresveratrol demonstrated the highest potency (IC50 = 4.2 μM) in reducing lipid content.
- Insulin-stimulated glucose uptake was improved by all analogues.
- Resveratrol and its methylated derivatives normalized mitochondrial activity, while oxyresveratrol had a lesser effect.
- Inhibition of SIRT1, PGC-1α, and JNK pathways attenuated the lipid-reducing effects.
- Autophagy played a significant role in the mechanism of action for most analogues, except oxyresveratrol.
Conclusions:
- Resveratrol and its analogues effectively reduce adipocyte lipid accumulation and improve glucose uptake.
- These compounds mimic caloric restriction through complex mechanisms involving SIRT1, PGC-1α, and JNK activation.
- The findings suggest that resveratrol and its derivatives are potential therapeutic candidates for obesity-related metabolic diseases.
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