Sulforaphane Regulates Glucose Metabolism Of Mice Fed With A High Fat Diet And The Mechanism

Background In the study, a high-fat diet induced obesity model was established using Nrf2knockout and wild mice to investigate the effect of sulforaphane on the glucose metabolism, andreveal the possible role of inulin signalling pathway. The current study may provide new way forcontrol obesity–related glucose metabolism disorder.Methods The genotype of Nrf2knockout mice was identified with PCR-gel electrophoresistest. The Nrf2knockout and wild mice were fed with high-fat diet to induce obesity, and obese-prone mice (hereinafter referred to as obese mice) were selected according to the body weight gain.Then the obese mice were divided into two subgroups, and treated with100μmol/kg bwsulforaphane diluted in saline or equal-volume saline by intragastric administration respectively.These mice continue to take high-fat diet. After6weeks, the glucose tolerance test was conducted.The serum was isolated from whole blood to detect biochemical markers, including ALT, AST,ALP, TG, CHOL, insulin, etc. and the insulin sensitivity index and insulin resistance index werecalculated. The expression of insulin signal pathway-related gene were measured by Western Blot.Results Wild-type and Nrf2knockout obese mice exhibit hepatic steatosis and enlarged fatcell size in inguinal adipose depot, with significant increase in inguinal and perirenal fat depots ofNrf2knockout mice (P<0.05). Sulforaphane treatment attenuates hepatic steatosis and decrease theadipocyte size in wild-type and Nrf2knockout obese mice.There is a significant increase of serum insulin (P<0.05) in obese mice, decrease of insulinsensitivity check index (P<0.05), and elevation of HOMA insulin resistance index (P<0.05) inwild-type and Nrf2knockout obese mice. Sulforaphane treatment do not affect the food intake ofall miceSulforaphane, but significantly attenuated the above-mentioned abnormal indicators(P<0.05). Western blotting showed a decreased expression of PI3K, p-Aktser473and GLUT4in liverand skeletal muscle. For wild-type obese mice, sulforaphane upregulted the hepatic level of IRβ,IRS-1, p-Aktser473, and GLUT4proteins, as well as IRS-1, PI3K, p-PDK1Ser241, p-Aktser473andGLUT4proteins level in skeletal muscle. For Nrf2knockout obese mice, sulforaphane treatmentinduced a remarkable increase in Akt, p-Aktser473,and downstream protein GLUT4, without theincrease in IRS-1, p-PDK1Ser241. Conclusions High-fat diet induced obesity inhibits insulin signalling in liver and skeletalmuscle, obesity-related hyperinsulinism and insulin resistance impair cellular glucose uptake.Sulforaphane treatment upregulates the expression of insulin signal pathway related genes,attenuates insulin resistance and abnormal glucose uptake in wild-type obese mice. The ablation ofNrf2may impair the SFN-induced attenuation of blood glucose and insulin resistance, with lesssignificant decrease of blood glucose and activation insulin signal pathway in Nrf2konckout obesemice treated with sulforaphane. It is known that SFN targets at Nrf2gene. Therefore, the studyshow that Nrf2mediates the SFN-induced attenuation of blood glucose and activation of insulinsignal pathway.