Transcriptional regulation of insulin action and sensitivity via a GSK3β-FBXW7-ERRα 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 ERRα preserves insulin sensitivity during diet-induced obesity. However, how ERRα 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 ERRα through a GSK3β/FBXW7 axis. Liver-specific deletion of GSK3β or FBXW7 or mice harboring mutations of ERRα phosphosites (ERRα3SA) co-targeted by GSK3β/FBXW7 result in accumulated ERRα proteins that no longer respond to insulin. ERRα3SA mice display reprogrammed liver and muscle transcriptomes, resulting in insulin resistance and compromised metabolic homeostasis, effects largely reversed by pharmacological inhibition of ERRα. These findings uncovered a previously unrecognised ERRα-dependent insulin regulatory pathway that could be targeted to improve insulin resistance and associated metabolic diseases. Liver RNA-sequencing data of WT and ERRα KO mice treated with saline or insulin as well as liver/muscle RNA-sequencing data of WT and ERRα3SA mice.