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Publication
Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis
in Mice.
Authors Zhang K, Guo X, Yan H, Wu Y, Pan Q, Shen JZ, Li X, Chen Y, Li L, Qi Y, Xu Z, Xie
W, Zhang W, Threadgill D, He L, Villarreal D, Sun Y, White MF, Zheng H, Guo S
Submitted By Submitted Externally on 4/7/2020
Status Published
Journal Endocrinology
Year 2019
Date Published 5/1/2019
Volume : Pages 160 : 1333 - 1347
PubMed Reference 30951171
Abstract 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 ß-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
a-cells/ß-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.




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