Novel mechanism of FOXO1 phosphorylation in glucagon signaling in control of glucose homeostasis

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

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2167-2182
Number of pages16
JournalDiabetes
Volume67
Issue number11
DOIs
StatePublished - Nov 1 2018

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Wu, Y., Pan, Q., Yan, H., Zhang, K., Guo, X., Xu, Z., Yang, W., Qi, Y., Guo, C. A., Hornsby, C., Zhang, L., Zhou, A., Li, L., Chen, Y., Zhang, W., Sun, Y., Zheng, H., Wondisford, F., He, L., & Guo, S. (2018). Novel mechanism of FOXO1 phosphorylation in glucagon signaling in control of glucose homeostasis. Diabetes, 67(11), 2167-2182. https://doi.org/10.2337/db18-0674