Browning of inguinal white adipose tissue by the novel lignan (-)-secoisolariciresinol 4-O-methyl ether attenuates diet-induced obesity through mitochondrial and peroxisomal activation.

Studies indicate that the induction and activation of brown and beige adipocytes, which can enhance energy expenditure, may be beneficial for managing obesity and its associated diseases. This study investigated whether a novel lignan (-)-secoisolariciresinol 4-O-methyl ether (S4M) obtained from arctigenin inhibited diet-induced obesity by the browning of white adipose tissue (WAT). S4M treatment inhibited adipogenesis and lipid accumulation in white-induced 3T3-L1 adipocytes and in zebrafish embryonic development. Moreover, S4M treatment promoted browning in white adipocytes by increasing TOM20, UCP1, and PGC1α protein levels and consequently upregulating the mitochondrial content. S4M treatment significantly promoted mitochondrial fission by increasing the expression of DRP1. Furthermore, it enhanced peroxisomal biogenesis and function by inducing PEX13, ACOX1, and catalase. Mdivi-1, a mitochondrial dynamics inhibitor, diminished the browning effect of white adipocytes by the S4M treatment. This study found that S4M treatment inhibited weight gain in high-fat diet-induced obese mice, decreased the weight of WAT, and increased the abundance and function of mitochondria and peroxisomes in inguinal WAT, suggesting that S4M treatment could increase energy expenditure. The results suggest that S4M has potential as a therapeutic agent for combating obesity and its associated metabolic disorders.