Pharmacology, pharmacogenomics, drug discovery and design, drug therapy
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.
