Hirsutenone Directly Targets PI3K and ERK to Inhibit Adipogenesis in 3T3‐L1 Preadipocytes

Abstract

Adipogenesis is a key driver of the expansion of adipose tissue mass that causes obesity. Hirsutenone (HST) is an active botanical diarylheptanoid present in Alnus species. In this study, we evaluated the effects of HST on adipogenesis, its mechanisms of action and the molecular targets involved. Using Oil Red O staining, we observed that HST dose-dependently suppresses lipid accumulation during adipogenesis in 3T3-L1 preadipocytes, concomitant with a decrease in peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and fatty acid synthase (FAS) protein expression. This inhibitory effect was largely limited to the early stage of adipogenesis, which includes mitotic clonal expansion (MCE), as evidenced by delayed cell cycle entry of preadipocytes from G1 to S phase. Furthermore, the regulation of MCE was accompanied by suppression of phosphatidylinositol 3-kinase (PI3K) and extracellular-regulated kinase (ERK) activity. HST was also shown to bind directly to PI3K and ERK1 in a non-ATP competitive manner. Our results suggest that HST attenuates adipogenesis by directly targeting PI3K and ERK during MCE in 3T3-L1 preadipocytes, underscoring the potential therapeutic application of HST in preventing obesity.

Diarylheptanoids from Alnus viridis ssp. viridis and Alnus glutinosa: Modulation of Quorum Sensing Activity in Pseudomonas aeruginosa

“…, aceroside VIII (4), and platyphyllenone (7). Platyphylloside (3), hirsutenone (5), and oregonin (6) were diarylheptanoids originated from the black alder.…”

“…Three of the diarylheptanoids (3, 4, and 5) negatively influenced the biosynthesis of pyocyanin, which is under the control of quorum sensing. Platyphyllenone (7) and hirsutenone (5) were able to inhibit the biosynthesis of violacein in C. violaceum CV026, with 5 being able to inhibit the synthesis of both biopigments.…”

“…Diarylheptanoids from Alnus viridis ssp. viridis and Alnus glutinosa: Modulation of Quorum Sensing Activity in Pseudomonas aeruginosa none) and green alder (platyphyllenone) and are well known for their anticancer, anti-inflammatory, and antioxidative properties [7][8][9][10][11][12].…”

Garcinia cambogia suppresses adipogenesis in 3T3‐L1 cells by inhibiting p90RSK and Stat3 activation during mitotic clonal expansion

“…Activation of signaling molecules including mitogen‐activated protein kinase (MAPK; Bost, Aouadi, Caron, & Binetruy, 2005), phosphoinositide 3‐kinase (PI3K)/Akt (Cheong et al, 2015; Huang, Liu, Guo, & Su, 2018), 5′‐adenosine monophosphate‐activated protein kinase (AMPK; Dagon, Avraham, & Berry, 2006; H. W. Lee, Rhee, Kim, & Pyo, 2018), Janus kinase (Jak)/signal transducer and activator of transcription (Stat; Richard & Stephens, 2014; Wang et al, 2009), and cAMP‐response element binding protein (CREB; Reusch, Colton, & Klemm, 2000) is critical for cell proliferation and differentiation during the early stages of adipogenesis. The hormonal inducers isobutylmethylxanthine, dexamethasone, insulin, and fetal bovine serum (FBS) stimulate adipogenesis in 3T3‐L1 cells and enhance early signaling‐pathway activation (Ruiz‐Ojeda, Ruperez, Gomez‐Llorente, Gil, & Aguilera, 2016).…”

18O-Tracer Metabolomics Reveals Protein Turnover and CDP-Choline Cycle Activity in Differentiating 3T3-L1 Pre-Adipocytes

“…Many natural products that inhibit adipogenesis in cell culture have been shown to act by affecting MCE. Rohitukine [ 8 ], hirsutenone [ 9 ], piceatannol [ 10 ], and dehydrodiconiferyl alcohol [ 11 ] are few among many natural products that have recently been found to inhibit adipogenesis by interfering with MCE. In view of recent findings that adipogenesis also occurs in adults, small-molecule inhibitors of adipogenesis that affect MCE may find clinical application in the treatment of obesity.…”