Transcriptional regulation of insulin action and sensitivity via a GSK3ß-FBXW7-ERRa axis

Insulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response for which transcriptional dysregulation is a major contributor. Genetic or pharmacological inhibition of the nuclear receptor ERRa preserves insulin sensitivity during diet-induced obesity. However, how ERRa integrates insulin signaling at the molecular level with whole body metabolism remains unknown. Herein, we reveal that insulin-mediated gene expression requires the nuclear stabilization of ERRa through a GSK3ß/FBXW7 axis. Liver-specific deletion of GSK3ß or FBXW7 or mice harboring mutations of ERRa phosphosites (ERRa3SA) co-targeted by GSK3ß/FBXW7 result in accumulated ERRa proteins that no longer respond to insulin. ERRa3SA mice display reprogrammed liver and muscle transcriptomes, resulting in insulin resistance and compromised metabolic homeostasis, effects largely reversed by pharmacological inhibition of ERRa. These findings uncovered a previously unrecognised ERRa-dependent insulin regulatory pathway that could be targeted to improve insulin resistance and associated metabolic diseases. Overall design: Liver RNA-sequencing data of WT and ERRa KO mice treated with saline or insulin as well as liver/muscle RNA-sequencing data of WT and ERRa3SA mice.