Multi-omics Insights into the Mitigation of Diet-induced Obesity by Dendrobium officinale Polysaccharides via Gut-Adipose Tissue Axis Modulation of Lipid Droplets

The rising prevalence of overweight and obesity poses a significant threat to life quality. Although <em>Dendrobium officinale</em> polysaccharide (DOP) has demonstrated various health benefits, its effects on obesity and the underlying mechanisms remain to be fully elucidated. This study, using a high-fat diet-induced obesity (DIO) mouse model, shows that DOP significantly alleviates DIO by suppressing lipid droplet (LD) expansion and downregulating LD-associated genes, including PLIN2 and PLIN3, in white adipose tissue (WAT). These genes positively correlate with metabolic parameters including body weight gain, adiposity, and glucose intolerance. A meta-analysis further reveals that PLIN2 and PLIN3 are consistently upregulated in the adipose tissues of both obese mice and humans, underscoring their clinical relevance. Transcriptomic analysis indicates that DOP potentially activates the Wnt signaling pathway in WAT, thereby suppressing lipid synthesis and storage and inhibiting adipocyte differentiation. Metagenomic analysis demonstrates that DOP reverses obesity-associated gut microbiota dysbiosis by downregulating bacteria positively associated with LD formation and obesity phenotypes, while upregulating bacteria negatively associated with these traits. Notably, a data-driven analysis identified <em>Bifidobacterium pseudolongum</em> and <em>B. choerinum</em> as potential key mediators of DOP's effects. Untargeted metabolomics reveals that DOP reshapes serum metabolite profiles, particularly upregulating acylcarnitines, which negatively correlate with LD formation and metabolic parameters. A multi-omics covariance network integrating gut microbiota, serum metabolites, WAT gene expression, and metabolic phenotypes suggests that DOP modulates lipid metabolism possibly through gut microbiota and metabolites, thereby improving obesity-related traits. In conclusion, this multi-omics study is the first to suggest that DOP may promote the Wnt signaling pathway and inhibit LD expansion through the gut-adipose axis, thereby mitigating the onset of DIO.