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

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 beta-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-S253(A/A) knockin mice, in which FoxO1-S253 alleles were replaced with alanine (A substitution) blocking FoxO1-S253 phosphorylation. FoxO1-S253(A/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 alpha-cells/beta-cells per islet. FoxO1-S253(A/A) mice exhibited a slight increase in energy expenditure but barely altered food intake and glucose uptake among tissues. Further analyses revealed that FoxO1-S253(A/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.