Zhang, Ya

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia resulting from progressive loss of β-cell insulin secretion frequently on the background of insulin resistance. T2DM, also known as non-insulin-dependent diabetes, accounts for more than 90% of all cases of diabetes. Insulin resistance (IR) refers to the reduced sensitivity of peripheral tissues to insulin and is one of the important triggers of type 2 diabetes. Sargassum fusiforme polysaccharide exhibits diverse biological activities, and more and more studies have shown it has a significant effect in improving insulin resistance with almost no side effects. Sargassum fusiforme fucoidan (SFF) is one of the main active components with active ingredients such as antioxidants and hypoglycemic lipids. However, the ameliorative effects of SFF on high-fat diet-induced insulin resistance mice and its underlying physiological mechanisms are not clear. Hence, the polysaccharides were extracted and purified from Sargassum fusiforme, and fucoidan (SFF), which has good antioxidant activity, was screened using a drosophila melanogaster aging model. The effect of SFF on the amelioration of insulin resistance in mice was investigated with a high-fat obese insulin resistance mice model. By gut microbiota and metabolomics techniques, the effect of SFF on intestinal metabolites and its mechanism of alleviate IR were investigated. After treatment with 200 mg/kg SFF for 8 weeks, it was found that SFF could reduce body weight, fasting blood glucose and homa-IR in insulin resistance mice. SFF could effectively activate Nrf2/ARE antioxidant signaling pathway in the liver and promote Nrf2 entry into the nucleus and downstream gene transcription. Metabolomics and intestinal microecology revealed that SFF could upregulate TUDCA level and downregulate ceramide level in mice colon and serum, and this change was dependent on gut microbiota. TUDCA effectively inhibits the FXR/SHP signaling pathway activated by a high-fat diet, thereby reducing the biosynthesis of enteric-derived ceramides. In addition, TUDCA in the liver could compete with Nrf2 to bind Keap1 to reduce the formation of the Nrf2/Keap1 complex, reduce Nrf2 ubiquitination, and thus contribute to Nrf2/ARE signaling activation. In conclusion, fucoidan from S. fusiforme was able to modulate gut microbiota, increased the levels of the intestinal metabolite TUDCA, reduced biosynthesis of entericderived ceramides and activated the Nrf2/ARE pathway, which in turn significantly improved insulin resistance induced by high-fat diet in mice. This study provides a new research idea for the study of brown algae fucoidan in metabolic diseases.