A new mechanism action of nuciferine to ameliorate high-fat diet-induced obesity: microbiota-dependent modulation of adipose browning and thermogenesis

Nuciferine (NUC) is a major porphine alkaloid derived from <em>Folium Nelumbinis</em> with anti-obesity activity. Our previous<em> in vitro</em> findings demonstrated that the beneficial effects of NUC were associated with its induction of thermogenic fat, although the specific mechanisms of action remain to be fully elucidated. Here, our results showed that NUC (12.8 and 25.6 mg/kg/day) treatment for 12 weeks could effectively attenuate weight gain, activate brown adipose tissues (BAT), and promote browning of inguinal white adipose tissues (iWAT) in high-fat diet (HFD)-fed mice. Subsequently, the 16S rRNA sequencing showed that NUC was effective in ameliorating the HFD-induced microbiota imbalance, and the specific genera (e.g., <em>Lachnoclostridium</em>, <em>Roseburia</em>, <em>Limosilactobacillus</em>, <em>Tyzzerella</em>, <em>Bilophila</em>, and <em>Weissella</em>) correlated strongly with brown-related features in BAT and iWAT. Meanwhile, metabolomics analysis revealed that NUC significantly increased the levels of microbial metabolites such as bile acids (e.g., taurocholic acid, chenodeoxycholic acid), myristic acid, and γ-linolenic acid, which have been previously described to turn fat “brown”. Importantly, <em>in vitro</em> experiments provided the first evidence of N-Acetylneuraminic acid (NANA)'s potential to activate brown adipocytes. Finally, a fecal microbiota transplantation (FMT) experiment identified that NUC-induced microbial alterations could increase energy expenditure (EE), BAT activity, and iWAT browning. Collectively, our findings demonstrated that NUC effectively promoted adipose browning and enhanced thermogenesis, linked to alterations in the gut microbiota and its metabolic byproducts, offering a novel therapeutic target for addressing obesity and associated metabolic disorders.