Syringaresinol activates the skeletal muscle SIRT1-FNDC5/irisin axis to enhance weight management

This study examined whether syringaresinol (SYR), a plant-derived lignan, modulates skeletal muscle SIRT1-related FNDC5/Irisin signaling and high-fat diet (HFD)-associated metabolic outcomes. Differentiated C2C12 myotubes were treated with SYR, the SIRT1 activator SRT1720, and the SIRT1 inhibitor EX-527 to assess Irisin-related readouts, mitochondrial-associated markers, gene expression, and SIRT1/PGC-1α protein abundance. In vivo, HFD-fed mice received low- or high-dose SYR by oral gavage for 18 weeks; body weight, food intake, plasma Irisin, lipid-related indices, and adipose-tissue gene expression were assessed. In C2C12 myotubes, SYR was associated with increased Irisin-related readouts, ATP content, citrate synthase activity, SIRT1/PGC-1α/FNDC5-related transcriptional changes, and higher SIRT1 and PGC-1α protein abundance. EX-527 attenuated SYR-associated responses, supporting involvement of SIRT1 signaling in the cellular model. In HFD-fed mice, SYR attenuated body-weight gain, increased circulating plasma Irisin, lowered the LDL-C/HDL-C ratio, and increased PGC-1α, Ucp1, and Pparγ expression in inguinal white adipose tissue without significantly changing food intake. SYR is associated with SIRT1/PGC-1α-related remodeling, Irisin-related readouts, and attenuated HFD-induced weight gain. These findings support SYR as a candidate nutritional modulator of muscle-adipose metabolic communication, while causal in vivo mediation by SIRT1, FNDC5, or Irisin requires further pathway-specific validation.