<i>Sargassum fusiforme</i> Fucoidan Ameliorates Obesity-Associated Metabolic Dysfunction via a Tauroursodeoxycholic Acid-Mediated TGR5-cAMP-PKA Signaling Pathway

The global rise in obesity necessitates new therapeutic strategies. This study, for the first time, elucidates a novel indirect mechanism for the metabolic benefits of <i>Sargassum fusiforme</i> fucoidan (SFF). We found that SFF administration to obese (<i>ob/ob</i>) mice, while showing no direct effect on adipocytes <i>in vitro</i>, led to a significant 6.3-fold increase in serum tauroursodeoxycholic acid (TUDCA). This SFF-induced TUDCA elevation was identified as the key mediator for improving systemic insulin resistance (IR) and white adipose tissue (WAT) inflammation. Mechanistic studies revealed that TUDCA directly counteracted palmitic acid-induced lipotoxicity in adipocytes by activating the G protein-coupled bile acid receptor 5 (TGR5) and its downstream cAMP-PKA signaling pathway. This activation suppressed NF-κB-driven inflammation and inhibited pro-inflammatory arachidonic acid/linoleic acid (AA/LA) catabolism. Crucially, the <i>in vivo</i> therapeutic effects of SFF were phenocopied by direct TUDCA administration. These findings reveal a novel fucoidan-TUDCA-TGR5 axis, identifying TGR5 signaling as a promising therapeutic target for obesity-related metabolic diseases.