Novel linked butanolide dimer compounds increase adiponectin production during adipogenesis in human mesenchymal stem cells through peroxisome proliferator-activated receptor γ modulation

Compounds inducing adiponectin production have therapeutic potential for metabolic diseases. During screening, heme oxygenase-1-inducing marliolide derivatives were identified as adiponectin-inducing compounds. Although some marliolide derivatives were directly bound to peroxisome proliferator-activated receptor γ (PPARγ), the adiponectin-inducing activity did not correlate with the PPARγ binding affinity. The most potent adiponectin inducing compound, (E,4S,5S)-3-butylidene-dihydro-4-hydroxy-5-methylfuran-2(3H)-one (1a), exhibited the weakest PPARγ binding activity. A docking simulation suggested that two 1a molecules can be present in two different sites within the PPARγ-ligand-binding pocket (LBP). Based on the docking model, novel linked butanolide dimer compounds were synthesized. A linked butanolide dimer compound, (3E,3′E,4S,4′S,5S,5′S)-3,3’-(decane-1,10-diylidene)bis(4-hydroxy-5-methyldihydrofuran-2(3H)-one) (3a), promoted adiponectin production in human bone marrow mesenchymal stem cells (hBM-MSCs) as a novel PPARγ full agonist (EC₅₀, 4.34 μM). This linked butanolide dimer study provides novel insight into PPARγ biology, suggesting that small molecules can form multiple ligand interactions within the PPARγ-LBP and thereby affect the functional outcomes of PPARγ activation.