Identification of adiponectin receptor agonist utilizing a fluorescence polarization based high throughput assay

Adiponectin, the adipose-derived hormone, plays an important role in the suppression of metabolic disorders that can result in type 2 diabetes, obesity, and atherosclerosis. It has been shown that up-regulation of Adiponectin or Adiponectin Receptor has a number of therapeutic benefits. Given that it is hard to convert the full size Adiponectin protein into a viable drug, Adiponectin Receptor agonists could be designed or identified using high-throughput screening. Here, we report on the development of a two-step screening process to identify Adiponectin agonists. First step, we developed a high throughput screening assay based on fluorescence polarization to identify Adiponectin ligands. The fluorescence polarization assay reported here could be adapted to screening against larger small molecular compound libraries. A natural product library containing 10,000 compounds was screened and 9 hits were selected for validation. These compounds have been taken for the second-step in vitro tests to confirm their agonistic activity. The most active Adiponectin Receptor 1 agonists are matairesinol, arctiin, (-)-arctigenin and gramine. The most active Adiponectin Receptor 2 agonists are parthenolide, taxifoliol, deoxyschizandrin, and syringin. These compounds may be useful drug candidates for hypoadiponectin related diseases.