Methyl gallate, a potent antioxidant inhibits mouse and human adipocyte differentiation and oxidative stress in adipocytes through impairment of mitotic clonal expansion

Abstract

Methyl gallate (MG) is a derivative of gallic acid and a potent antioxidant. In this study, we confirmed that MG treatment effectively inhibits lipid accumulation, which occurred mostly in the early stages of adipogenesis. We also showed that shortly after adipogenic induction, MG facilitated a G0/G1 cell cycle arrest. Mechanistic studies revealed that MG treatment inhibited ERK1/2 phosphorylation, which is a key regulator of the G1- to S-phase transition. Furthermore, MG treatment prevented the adipogenic hormonal stimuli-induced inhibition of the cyclin-dependent kinase inhibitor p27 . This led to inhibition of the transcription factor E2F1 by preventing the phosphorylation of, and thereby activation of its destruction partner RB. MG treatment also downregulated factors that are upstream of RB-E2F1 signaling such as Cdk2, Cyclin E, Cdk4, and Cyclin D1 where Cyclin D3 level was unaffected. We also found that MG treatment markedly decreased the expression and phosphorylation of C/EBPβ, by phosphorylating, and therefore inactivating, GSK3β, which is a prerequisite for its DNA binding capacity, and thereby mitotic clonal expansion (MCE). Ultimately, MG treatment downregulates key terminal adipogenic transcription factors including C/EBPα, PPARγ, aP2 (Fabp4), and adiponectin. Moreover, MG also protects adipocytes from oxidative stress by alleviating intracellular reactive oxygen species and activating Nrf2, HO-1, and PRDX3. Thus, this study provides a mechanistic insight into the anti-adipogenic actions of MG. © 2016 BioFactors, 42(6):716-726, 2016.

Constituents of Talisia nervosa with Potential Utility against Metabolic Syndrome

“…At the highest concentration of 50 µg/mL, the lipid content of adipocytes was increased to 58% and 68% by compounds 2 and 3, respectively, while rosiglitazone at a concentration of 3 µM increased adipogenesis by 100%, compared with the vehicle control. However, in a recent study, an inhibition of lipid accumulation in the early stages of adipogenesis by methyl gallate has been reported [18]. In contrast, compound 4 did not exhibit a significant increase in adipogenesis ( Figure 2) despite its PPARγ agonistic action.…”

Supplementation of Syzygium cumini seed powder prevented obesity, glucose intolerance, hyperlipidemia and oxidative stress in high carbohydrate high fat diet induced obese rats

“…Some of the phenolic antioxidants such as gallic acid and ellagic acid may prevent pre-adipocyte differentiation to adipocyte [53, 54]. The phenolic antioxidants gallic acid and ellagic acid present in Syzygium cumini seed powder could be responsible for the less adipose tissue deposition in high fat diet fed rats.…”

Wnt/β-catenin signaling plays a distinct role in methyl gallate–mediated inhibition of adipogenesis

“…In our previous study, we reported that MG inhibits adipocytic differentiation of murine 3T3-L1 cells and human subcutaneous preadipocytes by delaying their mitotic clonal expansion via control of the expression of cell cycle-regulatory proteins in the early phase of adipogenesis [14]. In the present study, we found that MG can prevent b-catenin degradation during adipocytic differentiation and later can promote its stabilization and localization to the nucleus.…”

“…It was recently reported that MG has a significant anti-inflammatory effect on zymosan-induced inflammation in experimental arthritis by reducing neutrophil migration, production of inflammatory mediators, and activation of cells crucial for the development of this disease [12]. We previously demonstrated that MG inhibits adipocytic differentiation and reduces reactive oxygen species (ROS)-mediated oxidative stress by impairing mitotic clonal expansion [14]. Nevertheless, the molecular mechanisms underlying the inhibition of key adipogenic transcription factors have yet to be deciphered.…”

“…A substantial number of reports revealed that a concentration of MG ranging from 1 to 100 mM exerts a wide range of biological actions such as antioxidant, antitumor, and antimicrobial effects without any significant toxicity toward a variety of animal cells in vitro and does not cause any other adverse effects in vivo [12,14]. It was recently reported that MG has a significant anti-inflammatory effect on zymosan-induced inflammation in experimental arthritis by reducing neutrophil migration, production of inflammatory mediators, and activation of cells crucial for the development of this disease [12].…”