Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis

Insulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response resulting from the dysregulation of a wide range of insulin-controlled cellular processes. However, how insulin affects cellular energy metabolism via long-term transcriptional regulation and whether boosting mitochondrial function alleviates insulin resistance remains to be elucidated. Herein we reveal that insulin directly enhances the activity of the nuclear receptor ERR alpha via a GSK3 beta/FBXW7 signaling axis. Liver-specific deletion of GSK3 beta or FBXW7 and mice harboring mutations of ERR alpha phosphosites (ERR alpha(3SA)) co-targeted by GSK3 beta/FBXW7 result in accumulated ERR alpha proteins that no longer respond to fluctuating insulin levels. ERR alpha(3SA) mice display reprogrammed liver and muscle transcriptomes, resulting in compromised energy homeostasis and reduced insulin sensitivity despite improved mitochondrial function. This crossroad of insulin signaling and transcriptional control by a nuclear receptor offers a framework to better understand the complex cellular processes contributing to the development of insulin resistance. The downstream mechanisms involved in insulin signaling and resistance remain incompletely understood. Here the authors report that insulin-dependent dephosphorylation stabilizes ERR alpha via the GSK3 beta/FBXW7 axis, and disruption of this post-translational mechanism results in insulin resistance in mice.

Automated summary

This study reveals the direct effect of insulin on cellular metabolism via regulating nuclear receptor ERRα activity through the GSK3β/FBXW7 signaling axis. Mice with ERRα(3SA) mutations exhibit altered transcriptomes and compromised energy balance, leading to reduced insulin sensitivity despite improved mitochondrial function.