Discovery of Pan-peroxisome Proliferator-Activated Receptor Modulators from an Endolichenic Fungus, Daldinia childiae

Adiponectin-synthesis-promoting compounds possess therapeutic potential to treat diverse metabolic diseases, including obesity and diabetes. Phenotypic screening to find adiponectin-synthesis-promoting compounds was performed using the adipogenesis model of human bone marrow mesenchymal stem cells. The extract of the endolichenic fungus Daldinia childiae 047215 significantly promoted adiponectin production. Bioactivity-guided isolation led to 13 active polyketides (1-13), which include naphthol monomers, dimers, and trimers. To the best of our knowledge, trimers of naphthol (1-4) have not been previously isolated as either natural or synthetic products. The novel naphthol trimer 3,1 ',3 ',3 ''-ternaphthalene-5,5 ',5 ''-trimethoxy-4,4 ',4 ''-triol (2) and a dimer, nodulisporin A (12), exhibited concentration-dependent adiponectin-synthesis-promoting activity (EC50 30.8 and 15.2 mu M, respectively). Compounds 2 and 12 bound to all three peroxisome proliferator-activated receptor (PPAR) subtypes, PPAR alpha, PPAR gamma, and PPAR delta. In addition, compound 2 transactivated retinoid X receptor alpha, whereas 12 did not. Naphthol oligomers 2 and 12 represent novel pan-PPAR modulators and are potential pharmacophores for designing new therapeutic agents against hypoadiponectinemia-associated metabolic diseases.

Automated summary

Compounds from an extract of an endolichenic fungus have the potential to promote adiponectin synthesis, making them promising candidates for treating metabolic diseases such as obesity and diabetes.