Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice.
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The transcription factor forkhead box O1 (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 S256 in human FOXO1 (FOXO1-S256), equivalent to S253 in mouse FoxO1 (FoxO1-S253), is a key phosphorylation site mediating the effect of insulin as a target of protein kinase B on suppression of FOXO1 activity and expression of target genes responsible for gluconeogenesis. Here, we investigated the role of FoxO1-S253 phosphorylation in control of glucose homeostasis in vivo by generating global FoxO1-S253A/A knockin mice, in which FoxO1-S253 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.
author list (cited authors)
Zhang, K., Guo, X., Yan, H., Wu, Y., Pan, Q., Shen, J. Z., ... Guo, S
complete list of authors
Zhang, Kebin||Guo, Xiaoqin||Yan, Hui||Wu, Yuxin||Pan, Quan||Shen, James Zheng||Li, Xiaopeng||Chen, Yunmei||Li, Ling||Qi, Yajuan||Xu, Zihui||Xie, Wei||Zhang, Weiping||Threadgill, David||He, Ling||Villarreal, Daniel||Sun, Yuxiang||White, Morris F||Zheng, Hongting||Guo, Shaodong