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

• DOI: 10.1038/s41467-022-29722-6
• Publication Date: 2022-04-19T10:04:03Z
• Authors: Hui Xia; Charlotte Scholtes; Catherine R. Dufour; Carlo Ouellet; Majid Ghahremani; Vincent Giguère
• Keywords: Energy homeostasis

Insulin resistance, a harbinger of the metabolic syndrome, is state compromised hormonal response resulting from dysregulation wide range insulin-controlled cellular processes. However, how insulin affects energy metabolism via long-term transcriptional regulation and whether boosting mitochondrial function alleviates resistance remains to be elucidated. Herein we reveal that directly enhances activity nuclear receptor ERRα GSK3β/FBXW7 signaling axis. Liver-specific deletion GSK3β or FBXW7 mice harboring mutations phosphosites (ERRα3SA) co-targeted by result in accumulated proteins no longer respond fluctuating levels. ERRα3SA display reprogrammed liver muscle transcriptomes, homeostasis reduced sensitivity despite improved function. This crossroad control offers framework better understand complex processes contributing development resistance.