Novel Mechanism of Foxo1 Phosphorylation in Glucagon Signaling in Control of Glucose Homeostasis. Academic Article uri icon


  • Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes. The pancreatic hormone glucagon increases and insulin suppresses HGP, controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser256 in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A-dependent phosphorylation of Foxo1 at Ser276 Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser276 phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser276 is a new target site identified in the control of Foxo1 bioactivity and associated metabolic diseases.

published proceedings

  • Diabetes

altmetric score

  • 55.508

author list (cited authors)

  • Wu, Y., Pan, Q., Yan, H., Zhang, K., Guo, X., Xu, Z., ... Guo, S.

citation count

  • 38

complete list of authors

  • Wu, Yuxin||Pan, Quan||Yan, Hui||Zhang, Kebin||Guo, Xiaoqin||Xu, Zihui||Yang, Wanbao||Qi, Yajuan||Guo, Cathy A||Hornsby, Caitlyn||Zhang, Lin||Zhou, Aimin||Li, Ling||Chen, Yunmei||Zhang, Weiping||Sun, Yuxiang||Zheng, Hongting||Wondisford, Fred||He, Ling||Guo, Shaodong

publication date

  • November 2018