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Endocrinology. 2019 May 1;160(5):1333-1347. doi: 10.1210/en.2018-00853.

Phosphorylation of Forkhead Protein FoxO1 at S253 Regulates Glucose Homeostasis in Mice.

Author information

1
Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas.
2
Xinqiao Hospital, Third Military Medical University, Chongqing, China.
3
Queens University Belfast School of Biological Sciences, Belfast, United Kingdom.
4
Division of Endocrinology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
5
Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts.

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 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.

PMID:
30951171
PMCID:
PMC6482038
DOI:
10.1210/en.2018-00853

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