3,3'-Diindolylmethane suppresses high-fat diet-induced obesity through inhibiting adipogenesis of pre-adipocytes by targeting USP2 activity

Mol Nutr Food Res. 2017 Oct;61(10). doi: 10.1002/mnfr.201700119. Epub 2017 Jul 18.


Scope: Indole-3-carbinol (I3C), a derivative abundant in cruciferous vegetables such as cabbage, is well known for its various health benefits such as chemo-preventive and anti-obesity effects. I3C is easily metabolized to 3,3'-diindolylmethane (DIM), a more stable form, in acidic conditions of the stomach. However, the anti-obesity effect of DIM has not been investigated clearly. We sought to investigate the effect of DIM on diet-induced obesity and to elucidate its underlying mechanisms.

Methods and results: High-fat diet (HFD)-fed obese mouse and MDI-induced 3T3-L1 adipogenesis models were used to study the effect of DIM. We observed that the administration of DIM (50 mg/kg BW) significantly suppressed HFD-induced obesity, associated with a decrease in adipose tissue. Additionally, we observed that DIM treatment (40 and 60 μM), but not I3C treatment, significantly inhibited MDI-induced adipogenesis by reducing the levels of several adipogenic proteins such as PPAR-γ and C/EBPα. DIM, but not I3C, suppressed cell cycle progression in the G1 phase, which occurred in the early stage of adipogenesis, inducing post-translational degradation of cyclin D1 by inhibiting ubiquitin specific peptidase 2 (USP2) activities.

Conclusion: Our findings indicate that cruciferous vegetables, which can produce DIM as a metabolite, have the potential to prevent or treat chronic obesity.

Keywords: 3,3’-Diindolylmethane; Cyclin D1; Indole-3-carbinol; Obesity; USP2 enzyme.

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipogenesis / drug effects*
  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Diet, High-Fat
  • Indoles / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / drug therapy*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases / antagonists & inhibitors
  • Ubiquitin-Specific Proteases / genetics*
  • Ubiquitin-Specific Proteases / metabolism


  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, mouse
  • Ccnd1 protein, mouse
  • Indoles
  • PPAR gamma
  • Cyclin D1
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases
  • Usp2 protein, mouse
  • 3,3'-diindolylmethane