Benzyl isothiocyanate ameliorates hepatic insulin resistance in mice with high-fat diet-induced nonalcoholic fatty liver disease.

The global prevalence of overweight and obesity has risen sharply over the past few decades as a result of excess calorie intake and sedentary lifestyles. Obesity increases the risk for various metabolic disorders, such as hyperlipidemia, fatty liver disease, and diabetes mellitus. Isothiocyanates, which are abundant in cruciferous vegetables, have been shown to exhibit anticancer, anti-inflammatory, and antioxidant properties. However, the efficacy of benzyl isothiocyanate (BITC) in preventing the adverse effects of obesity, such as hepatic steatosis and insulin resistance, remains uncertain. To address this knowledge gap, we assessed whether BITC protects against hepatic insulin resistance by using primary mouse hepatocytes and AML12 cells treated with palmitic acid (PA) and mice fed a high-fat diet supplemented with cholesterol and cholic acid (HFCCD). We found that the impairments in insulin sensitivity caused by PA, such as decreases in the phosphorylation of insulin receptor substrate (IRS) 1 (Tyr608), Akt, glycogen synthase kinase (GSK) 3β, and FOXO1 and increases in the expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase 1 (PEPCK) mRNA in hepatocytes, were mitigated by pretreatment with BITC. BITC also attenuated PA-induced hepatic lipid accumulation and reactive oxygen species production. In vivo, BITC significantly reduced blood glucose levels and the HOMA-IR and inhibited hepatic lipid accumulation, IRS1 phosphorylation at Ser307, and G6Pase and PEPCK expression compared with that in mice fed the HFCCD alone. These results show that BITC ameliorates the lipotoxicity associated with insulin resistance by activating the IR/IRS/Akt/FOXO1 and GSK3β pathways, which leads to decreased gluconeogenesis and increased glycogen synthesis.