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The estrogen-related receptorα(ERRα) is an orphan receptor belonging to the nuclear receptor superfamily.It plays a central rule in the regulation of the expression of mitochondrial oxidative phosphorylation (OXPHOS) genes.Thus,small-molecule ERRα agonists have been considered as new potential drugs for the treatment of metabolic diseases with poor energy balance.To date,no small-molecule agonists of ERRα have been identified despite several high-throughput screening campaigns.Herein,we repot the first potent and selective ERR agonist.Compound DK3 agonized ERR with EC50 <10 nM,while it did not show any potency on other nuclear receptors such as ERRβ,ERRγ,ER,ERβ or PPARγ/δ etc.In vitro and in vivo studies revealed that DK3 effectively enhanced insulin-dependent glucose uptake in muscle and alleviated high-fat-diet (HFD) induced glucose intolerance and hepatosteatosis in mice.Our study provided a promising lead compound for the further development of ERR agonists as new therapeutic agents.