Salicortin-Derivatives from Salix pseudo-lasiogyne Twigs Inhibit Adipogenesis in 3T3-L1 Cells via Modulation of C/EBP alpha and SREBP1c Dependent Pathway

Abstract

Obesity is reported to be associated with excessive growth of adipocyte mass tissue as a result of increases in the number and size of adipocytes differentiated from preadipocytes. To search for anti-adipogenic phytochemicals, we screened for inhibitory activities of various plant sources on adipocyte differentiation in 3T3-L1 preadipocytes. Among the sources, a methanolic extract of Salix pseudo-lasiogyne twigs (Salicaceae) reduced lipid accumulation in a concentration-dependent manner. During our search for anti-adipogenic constituents from S. pseudo-lasiogyne, five salicortin derivatives isolated from an EtOAc fraction of this plant and bearing 1-hydroxy-6-oxo-2-cyclohexenecarboxylate moieties, namely 2', 6'-O-acetylsalicortin (1), 2'-O-acetylsalicortin (2), 3'-O-acetylsalicortin (3), 6'-O-acetylsalicortin (4), and salicortin (5), were found to significantly inhibit adipocyte differentiation in 3T3-L1 cells. In particular, 2', 6'-O-acetylsalicortin (1) had the most potent inhibitory activity on adipocyte differentiation, with an IC50 value of 11.6 mu M, and it significantly down-regulated the expressions of CCAAT/enhancer binding protein alpha (C/EBP alpha) and sterol regulatory element binding protein 1 (SREBP1c). Furthermore, 2', 6'-O-acetylsalicortin (1) suppressed mRNA expression levels of C/EBP beta during the early stage of adipocyte differentiation and stearoyl coenzyme A desaturase 1 (SCD-1), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS) expression, target genes of SREBP1c. In the present study, we demonstrate that the anti-adipogenesis mechanism of 2',6'-O-acetylsalicortin (1) may be mediated via down-regulation of C/EBP alpha and SREBP1c dependent pathways. Through their anti-adipogenic activity, salicortin derivatives may be potential novel therapeutic agents against obesity.