Unravelling the synergy of curcumin and quercetin in the adipogenesis pathway: highlighting molecular dynamics and epigenetic reversibility.

Abstract

Obesity, the global pandemic, has been observed to be associated with metabolic diseases, including cardiovascular diseases, type 2 diabetes mellitus, polycystic ovarian syndrome, hypothyroidism, arthritis, and even cancer. Conventional drugs, popular in weight management, have been reported to have several adverse effects on cardiovascular and gastrointestinal health. Modern drug design, considering natural bioactive compounds with minimal side effects and ligand-receptor dynamic conformations, has become a necessity of the hour. In this context, the current study objective was to investigate the anti-obesity efficacy of two significant bioactive compounds, curcumin and quercetin, as potential therapeutics in obesity management. Molecular docking, followed by MD simulation, was the technique adopted in our study to identify the capability of curcumin and quercetin as potential anti-obesity drugs. GLP1R, PPARG, and LEPR were selected as the receptors. The structural stability of these proteins is required for their successful role in metabolic pathways. In vitro validation of the suitable doses of curcumin and quercetin was performed on 3T3L1 adipocytes. In-silico analyses, including root mean square deviation, radius of gyration, and solvent-accessible surface area, identified the specific ligand-dependent receptor activities. Quercetin was observed to enhance the compactness and stability of GLP1R and LEPR. In contrast, curcumin was found to maintain the conformation of PPARG. Treatment with a combination dose of curcumin and quercetin (15 µM + 20µM) on mature adipocytes for 72 hr reflected the most pronounced effects on the DNA methylation (4.83 ± 0.15%, p < 0.001), candidate gene expression (ADIPOQ: 0.00006 ± 0.00001-fold decrease; PPARG: 0.019 ± 0.0004-fold decrease; GLP1R: 0.096 ± 0.023-fold decrease; p < 0.001), and histone modifications. The prospects of this study include the consideration of a combination therapy of curcumin and quercetin for the most effective weight management outcome.