A natural Nrf2 activator glucoraphanin improves hepatic steatosis in high-fat diet-induced obese male mice associated with AMPK activation.

Genetic and pharmacological activation of the transcription factor nuclear factor, erythroid derived 2, like 2 (Nrf2) alleviates high-fat diet (HFD)-induced obesity in mice; however, synthetic Nrf2 activators are not clinically available due to safety concerns. Dietary glucoraphanin (GR), a naturally occurring compound found in cruciferous vegetables that activates Nrf2 and induces its target antioxidant genes. We previously demonstrated that GR increased thermogenesis and mitigated HFD-induced obesity in lean healthy mice. In this study, we investigated the therapeutic effects of GR on pre-existing obesity and associated metabolic disorders, such as hepatic steatosis, with or without low-fat dietary intervention. Eight-week-old male C57BL/6J mice were fed an HFD for 9 weeks to induce obesity. Subsequently, these obese mice were fed either the HFD or a normal chow diet, supplemented with or without GR, for an additional 11 weeks. GR supplementation did not decrease the body weight of HFD-fed mice; however, it significantly reduced plasma alanine aminotransferase and aspartate aminotransferase levels and hepatic triglyceride accumulation. These improvements in liver damage by GR were associated with decreased expression levels of fatty acid synthesis genes and proinflammatory chemokine genes, suppressed c-Jun N-terminal kinase activation, and reduced proinflammatory phenotypes of macrophages in the liver. Moreover, metabolome analysis identified increased hepatic levels of adenosine 5'-monophosphate (AMP) in HFD-GR mice compared with those in HFD mice, which agreed with increased phosphorylation levels of AMP-activated protein kinase. Our results show that GR may have a therapeutic potential for treating obesity-associated hepatic steatosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00658-6.