Widdrol Blocks 3T3-L1 Preadipocytes Growth and Differentiation Due to Inhibition of Mitotic Clonal Expansion

Abstract

Adipocyte differentiation is strongly associated with obesity, which causes metabolic disorders. In this study, we investigated the inhibitory effects of widdrol on 3T3-L1 preadipocyte growth and differentiation. Widdrol decreased lipid droplet accumulation and down-regulated adipogenic transcription factors such as C/EBPα, C/EBPβ, and PPARγ. Widdrol blocked preadipocyte proliferation and differentiation through the inhibition of mitotic clonal expansion, which was accompanied by the failure of degradation of p21, a cyclin-dependent kinase inhibitor. Cell-cycle analysis clearly indicated that widdrol actively induces cell-cycle arrest at the G1-S phage transition, causing cells to remain in the preadipocyte state. Moreover, widdrol increased p21 expression and inhibited Rb phosphorylation in preadipocyte incubated in a hormone medium. Therefore, these findings clearly suggest that widdrol blocks preadipocyte growth and differentiation through the inhibition of mitotic clonal expansion by p21and Rb-dependent G1 arrest and can be developed as a potent anti-adipogenic agent for reducing obesity.

Isobavachalcone from Angelica keiskei Inhibits Adipogenesis and Prevents Lipid Accumulation

“…Recently, many natural products have been reported to be anti-obesity agents that can inhibit MCE of 3T3-L1 adipocytes [ 2 ]. Widdrol and coagulanolides can arrest 3T3-L1 cells in the G1/S phase, while rohitukine can cause cell arrest in S/G2 [ 22 , 23 , 24 ]. Garcinol and pterostilbene can induce G2/M arrest by modulating the cell cycle regulators [ 25 ].…”

Processed Panax ginseng , sun ginseng, inhibits the differentiation and proliferation of 3T3-L1 preadipocytes and fat accumulation in Caenorhabditis elegans

“…In addition, Yun et al. [30] reported that widdrol, a natural sesquiterpene known as an anticancer and antifungal agent, suppressed preadipocyte proliferation by p21- and Rb-dependent G 1 arrest in 3T3-L1 preadipocytes. In this study, SG inhibited adipocyte proliferation during differentiation despite an early increase in the number of adipocytes (Fig.…”

Supplementation of All‐Trans‐Retinoic Acid Below Cytotoxic Levels Promotes Adipogenesis in 3T3‐L1 Cells

“…This causes MCE that eventually leads to the second round of confluency and exit from the cell cycle through entering the G0/G1‐phase for initiation of adipogenic differentiation (Green and Kehinde, ). It has been found that DNA replication is increased in 24 h (Gratzner et al, ) and cells are proliferated between 24 and 48 h after inducing preadipocyte differentiation in 3T3‐L1 cells (Kim et al, ; Tang et al, ; Yun et al, ). In agreement with aforementioned notion, cell proliferation occurred during the 2nd day of differentiation in the current study.…”

“…Disturbing cell cycle in this early stage has been known to inhibit adipogenic differentiation (Choi et al, ; Varshney et al, ), suggesting factors that affect the cell cycle can regulate adipogenesis. For example, 3T3‐L1 cells exposed to vitisin A or widdrol in the early differentiation stage (0–2 days since inducing differentiation) were inhibited in preadipocyte differentiation by regulating MCE and growth‐arrest (Kim et al, ; Yun et al, ). Although atRA at high concentrations (over 1 μM) generally inhibits proliferation of diverse cell types (Lin et al, ; Sandhu et al, ), it is still unclear whether atRA regulates cell proliferation during adipogenesis of 3T3‐L1 cells and consequently affects adipogenesis.…”