In vitro activation of brown adipocyte thermogenesis by fermented hypholomine B-enriched Sanghuangporus sanghuang mycelia through FNDC5/Irisin pathway.

In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented Sanghuangporus sanghuang mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in brown adipose tissue activation. Using HEK293 cells with FNDC5 promoter-EGFP constructs and differentiated 3T3-L1 adipocytes, we demonstrate that both compounds significantly enhance FNDC5 expression and irisin secretion. We reveal distinct mechanistic profiles: SS-IM1 showed superior efficacy in irisin induction and thermogenesis activation, while isolated hypholomine B demonstrated unprecedented potency in reducing lipid accumulation. Seahorse analysis revealed enhanced mitochondrial respiration and UCP1-mediated proton leak, confirming their thermogenic effects. Furthermore, we discovered that SS-IM1 uniquely enhanced glucose uptake through GLUT4 upregulation. These findings not only elucidate novel molecular mechanisms underlying the anti-obesity effects of S. sanghuang but also establish hypholomine B as a promising first-in-class therapeutic candidate for addressing the worldwide challenges of obesity and metabolic disorders.