Sulforaphane alleviates high fat diet-induced insulin resistance via AMPK/Nrf2/GPx4 axis

Biomed Pharmacother. 2022 Aug:152:113273. doi: 10.1016/j.biopha.2022.113273. Epub 2022 Jun 14.


Insulin resistance is a characteristic feature of type 2 diabetes. Sulforaphane (SFN) is a natural antioxidant extracted from the cruciferous vegetables. Recent study reported that SFN exhibits excellent anti-diabetic effects, however, the underlying mechanism is still unclear. This study aimed to investigate the therapeutic effects of SFN on a high-fat diet (HFD)-induced insulin resistance and potential mechanism. SFN was found to effectively reduce body weight, fasting blood glucose and hyperlipidemia, and improve liver function in HFD-fed mice. Furthermore, SFN effectively increased glucose uptake and improved insulin signaling in palmitic acid (PA)-induced HepG2 cells. SFN also led to increased expression of antioxidant genes downstream of Nrf2 and decreased accumulation of lipid peroxides MDA and 4-HNE, both in vivo and in vitro. Further studies revealed that SFN significantly reduced glutathione peroxidase 4 (GPx4) inactivation-mediated oxidative stress by activating the AMPK and Nrf2 signaling pathways. In PA-induced HepG2 cells and flies, the alleviation of insulin resistance by SFN was diminished by GPx4 inhibitor. Taken together, SFN ameliorated HFD-induced insulin resistance by activating the AMPK-Nrf2-GPx4 pathway, providing new insights into SFN as a therapeutic compound for the alleviation of insulin resistance.

Keywords: AMPK; GPx4; Insulin resistance; Nrf2; Oxidative stress; Sulforaphane.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Antioxidants / pharmacology
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diet, High-Fat / adverse effects
  • Insulin Resistance*
  • Isothiocyanates* / pharmacology
  • Isothiocyanates* / therapeutic use
  • Mice
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Sulfoxides* / pharmacology
  • Sulfoxides* / therapeutic use


  • AMP-Activated Protein Kinases
  • Antioxidants
  • Isothiocyanates
  • NF-E2-Related Factor 2
  • sulforaphane
  • Sulfoxides