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Diabetes. 2018 Nov;67(11):2167-2182. doi: 10.2337/db18-0674. Epub 2018 Sep 10.

Novel Mechanism of Foxo1 Phosphorylation in Glucagon Signaling in Control of Glucose Homeostasis.

Author information

1
Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX.
2
Department of Endocrinology, Third Military Medical University, Chongqing, China.
3
Division of Endocrinology, Department of Medicine, Johns Hopkins University, Baltimore, MD.
4
Department of Chemistry, Cleveland State University, Cleveland, OH.
5
Department of Nutrition and Food Science, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX shaodong.guo@tamu.edu.

Abstract

Dysregulation of hepatic glucose production (HGP) serves as a major underlying mechanism for the pathogenesis of type 2 diabetes. The pancreatic hormone glucagon increases and insulin suppresses HGP, controlling blood glucose homeostasis. The forkhead transcription factor Foxo1 promotes HGP through increasing expression of genes encoding the rate-limiting enzymes responsible for gluconeogenesis. We previously established that insulin suppresses Foxo1 by Akt-mediated phosphorylation of Foxo1 at Ser256 in human hepatocytes. In this study, we found a novel Foxo1 regulatory mechanism by glucagon, which promotes Foxo1 nuclear translocation and stability via cAMP- and protein kinase A-dependent phosphorylation of Foxo1 at Ser276 Replacing Foxo1-S276 with alanine (A) or aspartate (D) to block or mimic phosphorylation, respectively, markedly regulates Foxo1 stability and nuclear localization in human hepatocytes. To establish in vivo function of Foxo1-Ser276 phosphorylation in glucose metabolism, we generated Foxo1-S273A and Foxo1-S273D knock-in (KI) mice. The KI mice displayed impaired blood glucose homeostasis, as well as the basal and glucagon-mediated HGP in hepatocytes. Thus, Foxo1-Ser276 is a new target site identified in the control of Foxo1 bioactivity and associated metabolic diseases.

PMID:
30201683
PMCID:
PMC6198346
[Available on 2019-11-01]
DOI:
10.2337/db18-0674
[Indexed for MEDLINE]

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