| First Author | Xia H | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 2105 |
| PubMed ID | 35440636 | Mgi Jnum | J:342225 |
| Mgi Id | MGI:7265887 | Doi | 10.1038/s41467-022-29722-6 |
| Citation | Xia H, et al. (2022) Insulin action and resistance are dependent on a GSK3beta-FBXW7-ERRalpha transcriptional axis. Nat Commun 13(1):2105 |
| abstractText | 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 ERRalpha via a GSK3beta/FBXW7 signaling axis. Liver-specific deletion of GSK3beta or FBXW7 and mice harboring mutations of ERRalpha phosphosites (ERRalpha(3SA)) co-targeted by GSK3beta/FBXW7 result in accumulated ERRalpha proteins that no longer respond to fluctuating insulin levels. ERRalpha(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. |
