Phosphorylation of forkhead protein FoxO1 at Ser253 regulates glucose homeostasis in mice

Kebin Zhang, Xiaoqin Guo, Hui Yan, Yuxin Wu, Quan Pan, James Zheng Shen, Xiaopeng Li, Yunmei Chen, Ling Li, Yajuan Qi, Zihui Xu, Wei Xie, Weiping Zhang, David Threadgill, Ling He, Daniel Villarreal, Yuxiang Sun, Morris F White, Hongting Zheng, Shaodong Guo

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Abstract

The transcription factor forkhead boxO1 (FoxO1) is a key mediator in the insulin signaling pathway and controls multiple physiological functions, including hepatic glucose production (HGP) and pancreatic β-cell function. We previously demonstrated that Ser256 in human FOXO1, equivalent to Ser253 in mouse FoxO1, is a key phosphorylation site mediating the effect of insulin as a target of Akt on suppressing FOXO1 activity and expression of target genes responsible for gluconeogenesis. Here, we investigated the role of FoxO1-Ser253 phosphorylation in control of glucose hemostasis in vivo, by generating global FoxO1-S253A/A knock-in (KI) mice, in which FoxO1-Ser253 alleles were replaced with alanine (A substitution), blocking FoxO1-S253 phosphorylation. FoxO1-S253A/A mice displayed mild increases in feeding blood glucose and insulin levels, but decreases in fasting blood glucose and glucagon concentrations, as well as a reduction in the ratio of pancreatic α-cells/β-cells per islet. FoxO1-S253A/A mice exhibited a slight increase in energy expenditure, but barely altered food intake and glucose uptake among tissues. Further analyses revealed that FoxO1-S253A/A enhances FoxO1 nuclear localization and promotes the effect of glucagon on HGP. We conclude that dephosphorylation of S253 in FoxO1 may reflect a molecular basis of pancreatic plasticity during the development of insulin resistance.
Original languageEnglish
Article number1
Pages (from-to)1333-1347
Number of pages15
JournalEndocrinology
Volume160
Issue number5
DOIs
Publication statusPublished - 05 Apr 2019

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    Zhang, K., Guo, X., Yan, H., Wu, Y., Pan, Q., Shen, J. Z., Li, X., Chen, Y., Li, L., Qi, Y., Xu, Z., Xie, W., Zhang, W., Threadgill, D., He, L., Villarreal, D., Sun, Y., White, M. F., Zheng, H., & Guo, S. (2019). Phosphorylation of forkhead protein FoxO1 at Ser253 regulates glucose homeostasis in mice. Endocrinology, 160(5), 1333-1347. [1]. https://doi.org/10.1210/en.2018-00853