<i>Sargassum fusiforme</i> fucoidan alleviates diet-induced insulin resistance by inhibiting colon-derived ceramide biosynthesis

Abstract

<i>Sargassum fusiforme</i> fucoidan (SFF) is a highly sulfated heteropolysaccharide with various biological activities. As one of the causative factors of type 2 diabetes mellitus (T2DM), insulin resistance has become a global health issue. In this study, we investigated the potential pharmacological mechanisms by which SFF ameliorates insulin resistance in high-fat diet (HFD)-fed mice. SFF significantly enhanced tauroursodeoxycholic acid (TUDCA, a conjugated bile acid) levels and inhibited the farnesoid X receptor (FXR) signaling in the colon. SFF administration reduced ceramide levels in both serum and colonic tissue of HFD-fed mice, as well as reduced expression of <i>SPT</i> and <i>CerS</i> genes, which encode enzymes crucial to the biosynthesis of ceramides regulated by FXR signaling. Pearson's analysis showed that the TUDCA level was positively correlated with the gut bacteria <i>Clostridium</i>, and this was further validated in pseudo-germfree mice. Taken together, the results suggested that SFF increased TUDCA levels by remodeling gut microbiota, and TUDCA, a natural FXR antagonist, inhibited the FXR/SHP signaling pathway to reduce colon-derived biosynthesis of ceramide, thereby improving insulin resistance in the diet-induced obese (DIO) mice. This study has provided new insights into the therapeutic potential of <i>S. fusiforme</i> fucoidan in metabolic diseases.