Cladosporols, secondary metabolites from Cladosporium tenuissimum, have previously been characterized for their ability to control cell proliferation of human colon cancer cells through PPARγ-mediated mechanisms of action (1, 2). More recently, we demonstrated that cladosporol B, an oxidate form of cladosporol A, acts as a PPARγ partial agonist with lower affinity and reduced transactivation potential but sustained proapoptotic activity, as compared to the full agonists cladosporol A and rosiglitazone (3). We suggested that the lower transactivation potential, higher antiproliferative and sustained proapoptotic activity of cladosporol B can be ascribed to the different binding to PPARγ Identification of PPARγ partial agonists with no adverse side-effects as those reported for full agonists has received great attention for developing new therapeutical tools to manage obesity and diabetes. To this goal, we verified whether both cladosporols display regulatory properties in 3T3L1 preadipocytes by virtue of their differential binding to the PPARγbinding domain. We show here that cladosporols A and B hamper adipocyte differentiation and lipid storage through downregulation of mRNA and protein levels of early (C/EBP, PPARγand terminal (LPL, FAS, GLUT-4, Adiponectin, Leptin) differentiation markers. Analysis of stored triglycerides in 3T3L1 mature adipocytes and simultaneous release of glycerol and fatty acids in the culture medium upon cladosporols treatment indicate that both isoforms A and B inhibit lipogenesis. To our knowledge, this is the first report describing that cladosporol A and B, as PPARγ natural ligands, inhibit adipogenesis in vitro through modulation of early and late differentiation gene expression.
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