Discovery of a novel anti-obesity meroterpenoid agent targeted subcutaneous adipose tissue

Baisen Chen, Zhiqiang Shi, Yechun Wang, Minting Chen, Chunfang Yang, Hui Cui*, Tao Su*, Hiu Yee Kwan*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

2 Citations (Scopus)

Abstract

Background: Meroterpenoid furanasperterpene A (T2–3) with a novel 6/6/6/6/5 pentacyclic skeleton was isolated from the Aspergillus terreus GZU-31–1. Previously, we showed that T2–3 possessed significant lipid-lowering effects in 3T3-L1 adipocytes at 5 μM concentration. However, its therapeutic effect in metabolic disease and the underlying mechanisms of action remain unclear. Methods: High fat diet-induced obesity (DIO) mouse model and 3T3-L1 cell model were used to assess the anti-obesity effects of T2–3. Lipids in the adipocytes were examined by Oil Red O staining. β-catenin expression was examined by immunofluorescence and Western blotting, its activity was assessed by TOPflash/FOPflash assay. Results: T2–3 possessed potent anti-obesity effects in DIO mice, it significantly reduced body weight and subcutaneous adipose tissue (SAT) mass. Mechanistic studies showed that T2–3 significantly inhibited 3T3-L1 preadipocyte differentiation as indicated by the reduced number of mature adipocytes. The treatments also reduced the expressions of critical adipogenic transcription factors CEBP-α and PPAR-γ in both 3T3-L1 adipocytes and SAT in DIO mice. Interestingly, T2–3 increased the cytoplasmic and nuclear expressions of β-catenin and the transcriptional activity of β-catenin in 3T3-L1 adipocytes; the elevated β-catenin expression was also observed in SAT of the T2–3-treated DIO mice. Indeed, upregulation of β-catenin activity suppressed adipogenesis, while β-catenin inhibitor JW67 reversed the anti-adipogenic effect of T2–3. Taken together, our data suggest that T2–3 inhibits adipogenesis by upregulating β-catenin activity. Conclusions: Our study is the first report demonstrating meroterpenoid furanasperterpene A as a novel 6/6/6/6/5 pentacyclic skeleton (T2–3) that possesses potent anti-adipogenic effect by targeting β-catenin signaling pathway. Our findings drive new anti-obesity drug discovery and provide drug leads for chemists and pharmacologists.

Original languageEnglish
Article number154396
Number of pages12
JournalPhytomedicine
Volume106
DOIs
Publication statusPublished - Nov 2022

Scopus Subject Areas

  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine

User-Defined Keywords

  • CEPB-α
  • Obesity
  • PPAR-γ
  • Subcutaneous adipose tissue
  • T2–3
  • β-catenin

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