Orally administered octacosanol improves liver insulin resistance in high-fat diet-fed mice through the reconstruction of the gut microbiota structure and inhibition of the TLR4/NF-κB inflammatory pathway.

1-Octacosanol (Octa) is reported to possess many physiological properties. However, its relative mechanism has not been illustrated yet. Herein, we aimed to investigate the effect of Octa on insulin resistance in mice fed with a high fat diet (HFD) and used an in vitro simulated gastrointestinal tract to analyze its digestive behavior. The effects of Octa on the gut microbiota were verified by in vitro fermentation using the mouse fecal microbiota. As a result, the Octa monomer was digested into shortened saturated and unsaturated fatty acids (C10-C24) in the simulated gastrointestinal tract. Octa improved the fasting blood glucose (FBG), insulin resistance (IR), plasma lipids, and inflammatory response in HFD-fed mice in a dose-dependent manner. This study also suggested that a high-dose of Octa effectively decreased the levels of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in the plasma of HFD-fed mice. Octa improved the oxidative stress induced by a HFD and increased the expression of the Nrf2/ARE signaling pathway. Importantly, Octa reshaped gut microbiota through decreasing Firmicutes content and increasing Bacteroidota and Verrucomicrobiota contents at the phylum level, and the changes of intestinal flora structure caused by Octa were significantly correlated with the changes of inflammatory biomarkers. In conclusion, the effects of Octa on insulin resistance might be attributed to the reconstruction of the gut microbiota structure and inhibition of the TLR4/NF-κB inflammatory pathway in HFD-induced obese individuals.