<i>Sargassum fusiforme</i> Fucoidan Ameliorates Obesity-Associated Metabolic Dysfunction via a Tauroursodeoxycholic Acid-Mediated TGR5-cAMP-PKA Signaling Pathway
Hai Lin, Ya Zhang, Huanjuan Yan, Cheng Wang, Zhengshun Wen, Haibin Tong, Xiaoyan Pan
Abstract
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 Sargassum fusiforme fucoidan (SFF). We found that SFF administration to obese ( ob/ob ) mice, while showing no direct effect on adipocytes in vitro, 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 in vivo 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.