Dehydroleucodine inhibits mitotic clonal expansion during adipogenesis through cell cycle arrest

Abstract

Aberrant levels of preadipocyte differentiation, triggered by adipocyte hyperplasia and hypertrophy, results in the obesogenic phenotype. Obesity is a risk factor for several metabolic disorders. In this paper, dehydroleucodine inhibited the accumulation of lipid droplets and decreased the elevations of triglycerides, and this inhibitory effect occurred during the early stage of adipogenesis. Thus, not only did dehydroleucodine downregulate the expression of C/EBPα and PPARγ, it also strongly blocked the expression of C/EBPβ, an early stage biomarker of early adipogenesis, in a concentration-dependent manner. The proliferation of preadipocytes was dramatically suppressed when dehydroleucodine was added to the medium as early as 24 hr. These results indicate that dehydroleucodine may specifically affect mitotic clonal expansion to inhibit preadipocyte differentiation. Dehydroleucodine arrested the cell cycle at the G /G phase, increased p27 and decreased both cyclins A and D and their partners (e.g., CDK2 and CDK4). Additionally, dehydroleucodine decreased phosphorylation of Erk1/2 and Akt. Furthermore, dehydroleucodine downregulated expression of histone demethylase JMJD2B as well as repressed the expression of histone methyltransferase MLL4, which in turn diminished the expression of C/EBPβ and PPARγ, respectively. Collectively, our results indicate that dehydroleucodine inhibits preadipocyte differentiation by blocking mitotic clonal expansion via cell cycle arrest, which may be mediated by regulation of selective histone methylation/demethylation in transcription activation during the early step of adipogenesis.

Inula britannica Inhibits Adipogenesis of 3T3-L1 Preadipocytes via Modulation of Mitotic Clonal Expansion Involving ERK 1/2 and Akt Signaling Pathways

“…Additionally, IAE inhibited the expression of C/EBP-β and the activation of STAT3. Consistent with preceding results, previous studies have reported that plant extracts and their phytochemicals inhibit adipogenesis and lipid accumulation through suppression of MCE, which was dependent on the regulation of cell cycle progression and/or suppression of transcription factors [ 50 , 51 , 52 ]. For instance, Gleditsia sinensis fruit extract suppressed MCE and adipogenesis through the inhibition of p27 KIP1 degradation and the activation of STAT3 [ 7 ].…”

Puerarin protects against high‐fat high‐sucrose diet‐induced non‐alcoholic fatty liver disease by modulating PARP‐1/PI3K/AKT signaling pathway and facilitating mitochondrial homeostasis

“…These could be one of the mechanisms for puerarin to protect against HFHSinduced liver steatosis. PI3K/AKT signaling pathway is one of the most critical regulatory elements that modulate lipid metabolism (Abood, Veisaga, Lopez, & Barbieri, 2018;Huang et al, 2014). PI3K/AKT activation process could inhibit lipogenesis, retard excessive lipid deposition, and alleviate hepatic steatosis (Li et al, 2011).…”

Natural Products and Obesity: A Focus on the Regulation of Mitotic Clonal Expansion during Adipogenesis

“…Given the association between cell-cycle arrest and adipogenesis, Table 1 shows the effects of phytochemicals on the cell cycle, cell-cycle regulators, and lipid accumulation. Delphinidin, a major anthocyanin widely found in pigmented fruits and vegetables [97]; apigenin, isolated from the flavonoid-rich fraction of Daphne genkwa Siebold et Zuccarini crude extracts [98]; sinigrin, a glucosinolate [99]; curcumin, derived from an Asian spice herb, Curcuma longa , and curcumin-modified forms, bisdemethyoxy-curcumin and curcumin-3,4-dichloro phenyl pyrazole [100,101,102]; dehydroleucodine, isolated from the aerial parts of Artemisia douglasiana [103]; sulforaphane, a naturally occurring isothiocyanate compound, produced in cruciferous vegetables such as broccoli and cabbage [67]; vitisin A, a resveratrol tetramer plentiful in the stembark of Vitis [104]; ellagic acid, present in raspberries, strawberries, walnuts, and pomegranate [105]; and oleuropein and hydroxytrosol, phenolic compounds [106] significantly inhibit intracellular lipid accumulation by increasing the cell population in the G0/G1 phase. Cell-cycle-arrested preadipocytes in the G1 phase of the cell cycle are associated with CDK inhibitory proteins, such as p21 CIP and p27 KIP1 , and Rb phosphorylation [24].…”

“…Cell-cycle-arrested preadipocytes in the G1 phase of the cell cycle are associated with CDK inhibitory proteins, such as p21 CIP and p27 KIP1 , and Rb phosphorylation [24]. Indeed, delphinidin, dehydroleucodine, bisdemethyoxy-curcumin, curcumin-3,4-dichloro phenyl pyrazole, apigenin, sinigrin, sulforaphane, and vitisin A upregulate p21 CIP and/or p27 KIP1 expression [67,97,98,99,102,103,104,107]. With the concomitant increase of cell number in the G0/G1 phase, decreased phosphorylation of Rb is observed in sulforaphane-, vitisin A-, or ellagic acid-treated cells [67,104,105].…”