Current Diabetes Reports

, Volume 9, Issue 3, pp 208–214 | Cite as

The role of FOXO in the regulation of metabolism

  • Danielle N. Gross
  • Min Wan
  • Morris J. BirnbaumEmail author


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 insulinresponsive tissues will strengthen our understanding and allow us to better combat insulin resistance and diabetes mellitus.


Hepatic Glucose Production Transcription Factor FoxO1 Irs2 Muscle Precursor Cell Nuclear Exclusion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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References and Recommended Reading

  1. 1.
    Liu Y, Dentin R, Chen D, et al.: A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 2008, 456:269–273.PubMedCrossRefGoogle Scholar
  2. 2.
    Matsumoto M, Pocai A, Rossetti L, et al.: Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor foxo1 in liver. Cell Metab 2007, 6:208–216.PubMedCrossRefGoogle Scholar
  3. 3.
    Nakae J, Cao Y, Daitoku H, et al.: The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. J Clin Invest 2006, 116:2473–2483.PubMedGoogle Scholar
  4. 4.
    Qu S, Altomonte J, Perdomo G, et al.: Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology 2006, 147:5641–5652.PubMedCrossRefGoogle Scholar
  5. 5.
    Li X, Monks B, Ge Q, Birnbaum MJ: Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 2007, 447:1012–1016.PubMedCrossRefGoogle Scholar
  6. 6.
    Zhang W, Patil S, Chauhan B, et al.: FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 2006, 281:10105–10117.PubMedCrossRefGoogle Scholar
  7. 7.
    Matsumoto M, Han S, Kitamura T, Accili D: Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 2006, 116:2464–2472.PubMedGoogle Scholar
  8. 8.
    Altomonte J, Richter A, Harbaran S, et al.: Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab 2003, 285:E718–E728.PubMedGoogle Scholar
  9. 9.
    Samuel VT, Choi CS, Phillips TG, et al.: Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes 2006, 55:2042–2050.PubMedCrossRefGoogle Scholar
  10. 10.
    Dong XC, Copps KD, Guo S, et al.: Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 2008, 8:65–76.PubMedCrossRefGoogle Scholar
  11. 11.
    Kubota N, Kubota T, Itoh S, et al.: Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab 2008, 8:49–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Housley MP, Rodgers JT, Udeshi ND, et al.: O-GlcNAc regulates FoxO activation in response to glucose. J Biol Chem 2008, 283:16283–16292.PubMedCrossRefGoogle Scholar
  13. 13.
    Housley MP, Udeshi ND, Rodgers JT, et al.: A PGC-1{alpha}-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J Biol Chem 2009, 284:5148–5157.PubMedCrossRefGoogle Scholar
  14. 14.
    Kamagate A, Qu S, Perdomo G, et al.: FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. J Clin Invest 2008, 118:2347–2364.PubMedGoogle Scholar
  15. 15.
    Altomonte J, Cong L, Harbaran S, et al.: Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest 2004, 114:1493–1503.PubMedGoogle Scholar
  16. 16.
    Gross DN, van den Heuvel AP, Birnbaum MJ: The role of FoxO in the regulation of metabolism. Oncogene 2008, 27:2320–2336.PubMedCrossRefGoogle Scholar
  17. 17.
    Kitamura T, Nakae J, Kitamura Y, et al.: The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 2002, 110:1839–1847.PubMedGoogle Scholar
  18. 18.
    Essers M, Weijzen S, De Vries-Smits A, et al.: FOXO transcription factor activation by oxidative stress mediated by the small TPase Ral and JNK. EMBO J 2004, 23:4802–4812.PubMedCrossRefGoogle Scholar
  19. 19.
    Kawamori D, Kajimoto Y, Kaneto H, et al.: Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase. Diabetes 2003, 52:2896–2904.PubMedCrossRefGoogle Scholar
  20. 20.
    Kawamori D, Kaneto H, Nakatani Y, et al.: The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem 2006, 281:1091–1098.PubMedCrossRefGoogle Scholar
  21. 21.
    Salih DA, Brunet A: FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 2008, 20:126–136.PubMedCrossRefGoogle Scholar
  22. 22.
    Kitamura YI, Kitamura T, Kruse JP, et al.: FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab 2005, 2:153–163.PubMedCrossRefGoogle Scholar
  23. 23.
    Daitoku H, Hatta M, Matsuzaki H, et al.: Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci U S A 2004, 101:10042–10047.PubMedCrossRefGoogle Scholar
  24. 24.
    Rulifson IC, Karnik SK, Heiser PW, et al.: Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A 2007, 104:6247–6252.PubMedCrossRefGoogle Scholar
  25. 25.
    Essers M, de Vries-Smits LM, Barker N, et al.: Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 2005, 308:1181–1184.PubMedCrossRefGoogle Scholar
  26. 26.
    Hoogeboom D, Essers M, Polderman PE, et al.: Interaction of FOXO with beta-catenin inhibits beta-catenin/T cell factor activity. J Biol Chem 2008, 283:9224–9230.PubMedCrossRefGoogle Scholar
  27. 27.
    Jin T: The WNT signalling pathway and diabetes mellitus. Diabetologia 2008, 51:1771–1780.PubMedCrossRefGoogle Scholar
  28. 28.
    Liu Z, Habener JF: Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem 2008, 283:8723–8735.PubMedCrossRefGoogle Scholar
  29. 29.
    Nakae J, Kitamura T, Kitamura Y, et al.: The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell 2003, 4:119–129.PubMedCrossRefGoogle Scholar
  30. 30.
    Armoni M, Harel C, Karni S, et al.: 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, 281:19881–19891.PubMedCrossRefGoogle Scholar
  31. 31.
    Dowell P, Otto TC, Adi S, Lane MD: Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem 2003, 278:45485–45491.PubMedCrossRefGoogle Scholar
  32. 32.
    Nakae J, Cao Y, Oki M, et al.: Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure. Diabetes 2008, 57:563–576.PubMedCrossRefGoogle Scholar
  33. 33.
    Jing E, Gesta S, Kahn CR: SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab 2007, 6:105–114.PubMedCrossRefGoogle Scholar
  34. 34.
    Wang F, Tong Q: SIRT2 suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARgamma. Mol Biol Cell 2009, 20:801–808.PubMedCrossRefGoogle Scholar
  35. 35.
    Picard F, Kurtev M, Chung N, et al.: Sirt1 promotes fat mobilization in white adipocytes by repressing PPARgamma. Nature 2004, 429:771–776.PubMedCrossRefGoogle Scholar
  36. 36.
    Subauste AR, Burant CF: Role of FoxO1 in FFA-induced oxidative stress in adipocytes. Am J Physiol Endocrinol Metab 2007, 293:E159–E164.PubMedCrossRefGoogle Scholar
  37. 37.
    Bois PR, Grosveld GC: FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts. EMBO J 2003, 22:1147–1157.PubMedCrossRefGoogle Scholar
  38. 38.
    Hu P, Geles KG, Paik JH, et al.: Codependent activators direct myoblast-specific MyoD transcription. Dev Cell 2008, 15:534–546.PubMedCrossRefGoogle Scholar
  39. 39.
    Lees SJ, Childs TE, Booth FW: Age-dependent FOXO regulation of p27Kip1 expression via a conserved binding motif in rat muscle precursor cells. Am J Physiol Cell Physiol 2008, 295:C1238–C1246.PubMedCrossRefGoogle Scholar
  40. 40.
    Kitamura T, Kitamura YI, Funahashi Y, et al.: A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J Clin Invest 2007, 117:2477–2485.PubMedCrossRefGoogle Scholar
  41. 41.
    Hribal ML, Nakae J, Kitamura T, et al.: Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors. J Cell Biol 2003, 162:535–541.PubMedCrossRefGoogle Scholar
  42. 42.
    Wu AL, Kim JH, Zhang C, et al.: Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mammalian target of rapamycin pathway components. Endocrinology 2008, 149:1407–1414.PubMedCrossRefGoogle Scholar
  43. 43.
    Kamei Y, Miura S, Suzuki M, et al.: Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem 2004, 279:41114–41123.PubMedCrossRefGoogle Scholar
  44. 44.
    Southgate RJ, Neill B, Prelovsek O, et al.: FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. J Biol Chem 2007, 282:21176–21186.PubMedCrossRefGoogle Scholar
  45. 45.
    Allen DL, Unterman TG: Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am J Physiol Cell Physiol 2007, 292:C188–C199.PubMedCrossRefGoogle Scholar
  46. 46.
    Furuyama T, Kitayama K, Yamashita H, Mori N: Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J 2003, 375:365–371.PubMedCrossRefGoogle Scholar
  47. 47.
    Waddell DS, Baehr LM, van den Brandt J, et al.: The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am J Physiol Endocrinol Metab 2008, 295:E785–E797.PubMedCrossRefGoogle Scholar
  48. 48.
    Wang X, Hu Z, Hu J, et al.: Insulin resistance accelerates muscle protein degradation: activation of the ubiquitinproteasome pathway by defects in muscle cell signaling. Endocrinology 2006, 147:4160–4168.PubMedCrossRefGoogle Scholar
  49. 49.
    Sandri M, Sandri C, Gilbert A, et al.: Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004, 117:399–412.PubMedCrossRefGoogle Scholar
  50. 50.
    Mammucari C, Milan G, Romanello V, et al.: FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 2007, 6:458–471.PubMedCrossRefGoogle Scholar
  51. 51.
    Zhao J, Brault JJ, Schild A, et al.: FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007, 6:472–483.PubMedCrossRefGoogle Scholar
  52. 52.
    Kim M, Pak Y, Jang P, et al.: Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat Neurosci 2006, 9:901–906.PubMedCrossRefGoogle Scholar
  53. 53.
    Kitamura T, Feng Y, Kitamura YI, et al.: Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nat Med 2006, 12:534–540.PubMedCrossRefGoogle Scholar
  54. 54.
    Fukuda M, Jones JE, Olson D, et al.: Monitoring FoxO1 localization in chemically identified neurons. J Neurosci 2008, 28:13640–13648.PubMedCrossRefGoogle Scholar
  55. 55.
    Belgardt BF, Husch A, Rother E, et al.: PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response. Cell Metab 2008, 7:291–301.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Danielle N. Gross
  • Min Wan
  • Morris J. Birnbaum
    • 1
    Email author
  1. 1.University of Pennsylvania School of MedicinePhiladelphiaUSA

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