The Role of FOXO in the Regulation of Metabolism

Overview

Journal Curr Diab Rep

Publisher Current Science

Specialty Endocrinology

Date 2009 Jun 4

PMID 19490822

Citations 111

Authors

Danielle N Gross

Min Wan

Morris J Birnbaum

Affiliations

Soon will be listed here.

Abstract

Forkhead box O (FOXO) transcription factors play an important role in modulating metabolic functions. FOXO is regulated by several modifications, but one of the most critical is phosphorylation and nuclear exclusion by Akt. Given the impact of insulin signaling on Akt-mediated phosphorylation of FOXO and the relatively high expression of Foxo1 in insulin-responsive tissues, this transcription factor is highly poised to regulate energy metabolism. When nutrient and insulin levels are low, Foxo1 promotes expression of gluconeogenic enzymes. Conversely, in the fed state, insulin levels rise and stimulate uptake of glucose primarily into skeletal muscle and other organs, including adipose tissue. Under certain pathophysiologic conditions, including insulin resistance, negative signaling to Foxo1 is compromised. Further clarification of the role of Foxo1 in insulin-responsive tissues will strengthen our understanding and allow us to better combat insulin resistance and diabetes mellitus.

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References

Wu A, Kim J, Zhang C, Unterman T, Chen J . Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components. Endocrinology. 2007; 149(3):1407-14. PMC: 2275355. DOI: 10.1210/en.2007-1470. View

Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M . Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A. 2004; 101(27):10042-7. PMC: 454161. DOI: 10.1073/pnas.0400593101. View

Nakae J, Cao Y, Daitoku H, Fukamizu A, Ogawa W, Yano Y . The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. J Clin Invest. 2006; 116(9):2473-83. PMC: 1550275. DOI: 10.1172/JCI25518. View

Kim M, Pak Y, Jang P, NamKoong C, Choi Y, Won J . Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat Neurosci. 2006; 9(7):901-6. DOI: 10.1038/nn1731. View

Samuel V, Choi C, Phillips T, Romanelli A, Geisler J, Bhanot S . Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes. 2006; 55(7):2042-50. DOI: 10.2337/db05-0705. View

Kawamori D, Kaneto H, Nakatani Y, Matsuoka T, Matsuhisa M, Hori M . The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem. 2005; 281(2):1091-8. DOI: 10.1074/jbc.M508510200. View

Armoni M, Harel C, Karni S, Chen H, Bar-Yoseph F, Ver M . FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity. J Biol Chem. 2006; 281(29):19881-91. DOI: 10.1074/jbc.M600320200. View

Belgardt B, Husch A, Rother E, Ernst M, Wunderlich F, Hampel B . PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab. 2008; 7(4):291-301. DOI: 10.1016/j.cmet.2008.01.006. View

Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A . Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004; 117(3):399-412. PMC: 3619734. DOI: 10.1016/s0092-8674(04)00400-3. View

10.

Liu Z, Habener J . Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem. 2008; 283(13):8723-35. PMC: 2417166. DOI: 10.1074/jbc.M706105200. View

11.

Fukuda M, Jones J, Olson D, Hill J, Lee C, Gautron L . Monitoring FoxO1 localization in chemically identified neurons. J Neurosci. 2008; 28(50):13640-8. PMC: 2615536. DOI: 10.1523/JNEUROSCI.4023-08.2008. View

12.

Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S . A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature. 2008; 456(7219):269-73. PMC: 2597669. DOI: 10.1038/nature07349. View

13.

Li X, Monks B, Ge Q, Birnbaum M . Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature. 2007; 447(7147):1012-6. DOI: 10.1038/nature05861. View

14.

Kitamura T, Ido Kitamura Y, Funahashi Y, Shawber C, Castrillon D, Kollipara R . A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J Clin Invest. 2007; 117(9):2477-85. PMC: 1950461. DOI: 10.1172/JCI32054. View

15.

Housley M, Udeshi N, Rodgers J, Shabanowitz J, Puigserver P, Hunt D . A PGC-1alpha-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J Biol Chem. 2008; 284(8):5148-57. PMC: 2643526. DOI: 10.1074/jbc.M808890200. View

16.

Jing E, Gesta S, Kahn C . SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 2007; 6(2):105-14. PMC: 2083635. DOI: 10.1016/j.cmet.2007.07.003. View

17.

Southgate R, Neill B, Prelovsek O, El-Osta A, Kamei Y, Miura S . FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. J Biol Chem. 2007; 282(29):21176-86. DOI: 10.1074/jbc.M702039200. View

18.

Ido Kitamura Y, Kitamura T, Kruse J, Raum J, Stein R, Gu W . FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab. 2005; 2(3):153-63. DOI: 10.1016/j.cmet.2005.08.004. View

19.

Qu S, Altomonte J, Perdomo G, He J, Fan Y, Kamagate A . Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology. 2006; 147(12):5641-52. PMC: 2665253. DOI: 10.1210/en.2006-0541. View

20.

Housley M, Rodgers J, Udeshi N, Kelly T, Shabanowitz J, Hunt D . O-GlcNAc regulates FoxO activation in response to glucose. J Biol Chem. 2008; 283(24):16283-92. PMC: 2423255. DOI: 10.1074/jbc.M802240200. View