Vol 10, No 3 (2021)
Review article
Published online: 2021-03-05
The role of FOXO transcription factors in development of type 2 diabetes and potential therapeutic possibilities
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Clin Diabetol 2021;10(3):290-298.
Abstract
Forkhead box class O (FOXO) family member proteins
are key transcription factors for maintaining the intracellular
homeostasis in response to changes in the
internal and external environment. They participate in
the control of such cellular processes as proliferation,
cell cycle, apoptosis, glucose and lipid metabolism,
and oxidative stress response. Altered expression and
activity of these factors are associated with development
of metabolic disturbances, primarily type 2
diabetes. Understanding of the role of FOXO in the
pathophysiology of these abnormalities will enable
appropriate steps to prevent their development and to
create therapies targeted at the disturbances underlying
type 2 diabetes and metabolic syndrome. In the
present article, we summarized the current knowledge
about the physiology and pathophysiology of these
transcription factors and described their role in the
development of diabetes and functioning of various
organs. We focused on their role in progression of
diabetes and indicated potential targets for future
therapeutic interventions.
Keywords: diabetesFOXO transcription factorsb-cell failureglucose metabolismlipid metabolisminsulin signalling pathwayoxidative stress
References
- Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004; 117(4): 421–426.
- Eijkelenboom A, Burgering BMT. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013; 14(2): 83–97.
- Lam EWF, Brosens JJ, Gomes AR, et al. Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer. 2013; 13(7): 482–495.
- Kaestner KH, Knochel W, Martinez DE. Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev. 2000; 14(2): 142–146.
- van der Vos KE, Coffer PJ. The extending network of FOXO transcriptional target genes. Antioxid Redox Signal. 2011; 14(4): 579–592.
- Brent MM, Anand R, Marmorstein R. Structural basis for DNA recognition by FoxO1 and its regulation by posttranslational modification. Structure. 2008; 16(9): 1407–1416.
- Hwangbo DS, Gershman B, Gersham B, et al. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature. 2004; 429(6991): 562–566.
- Matsumoto M, Han S, Kitamura T, et al. Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest. 2006; 116(9): 2464–2472.
- Yoon JC, Puigserver P, Chen G, et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature. 2001; 413(6852): 131–138.
- Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature. 2003; 423(6939): 550–555.
- Haeusler RA, Kaestner KH, Accili D. FoxOs function synergistically to promote glucose production. J Biol Chem. 2010; 285(46): 35245–35248.
- Roth U, Curth K, Unterman TG, et al. The transcription factors HIF-1 and HNF-4 and the coactivator p300 are involved in insulin-regulated glucokinase gene expression via the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2004; 279(4): 2623–2631.
- Haeusler RA, Hartil K, Vaitheesvaran B, et al. Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors. Nat Commun. 2014; 5: 5190.
- Kamagate A, Qu S, Perdomo G, et al. FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. J Clin Invest. 2008; 118(6): 2347–2364.
- 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(3): 208–216.
- Lu M, Wan M, Leavens KF, et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med. 2012; 18(3): 388–395.
- Nakae J, Biggs WH, Kitamura T, et al. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet. 2002; 32(2): 245–253.
- Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004; 116(4): 551–563.
- Mihaylova MM, Vasquez DS, Ravnskjaer K, et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell. 2011; 145(4): 607–621.
- Altomonte J, Cong L, Harbaran S, et al. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest. 2004; 114(10): 1493–1503.
- Gordts PL, Nock R, Son NH, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest. 2016; 126(8): 2855–2866.
- Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet. 1999; 354(9173): 141–148.
- Kanter JE, Shao B, Kramer F, et al. Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes. J Clin Invest. 2019; 129(10): 4165–4179.
- Haeusler RA, Pratt-Hyatt M, Welch CL, et al. Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia. Cell Metab. 2012; 15(1): 65–74.
- Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptor for bile acids. Science. 1999; 284(5418): 1362–1365.
- Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem. 2006; 281(52): 39915–39924.
- Nakae J, Kitamura T, Kitamura Y, et al. The forkhead transcription factor foxo1 regulates adipocyte differentiation. Developmental Cell. 2003; 4(1): 119–129.
- Dowell P, Otto TC, Adi S, et al. Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem. 2003; 278(46): 45485–45491.
- Liu L, Zheng LD, Zou P, et al. FoxO1 antagonist suppresses autophagy and lipid droplet growth in adipocytes. Cell Cycle. 2016; 15(15): 2033–2041.
- Wang QA, Tao C, Gupta RK, et al. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013; 19(10): 1338–1344.
- Fu Y, Luo N, Klein RL, et al. Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. J Lipid Res. 2005; 46(7): 1369–1379.
- Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem. 2006; 281(52): 39915–39924.
- Nakae J, Cao Y, Hakuno F, et al. Novel repressor regulates insulin sensitivity through interaction with Foxo1. EMBO J. 2012; 31(10): 2275–2295.
- Nakae J, Cao Y, Oki M, et al. Forkhead transcription factor FoxO1 in adipose tissue regulates energy storage and expenditure. Diabetes. 2008; 57(3): 563–576.
- Ahlgren U, Jonsson J, Jonsson L, et al. beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes. Genes Dev. 1998; 12(12): 1763–1768.
- Kitamura T, Kitamura YI, Kobayashi M, et al. Regulation of pancreatic juxtaductal endocrine cell formation by FoxO1. Mol Cell Biol. 2009; 29(16): 4417–4430.
- 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(12): 1839–1847.
- Pajvani UB, Accili D, Pajvani UB, et al. The new biology of diabetes. Diabetologia. 2015; 58(11): 2459–2468.
- Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination. Diabetes. 2000; 49(5): 677–683.
- Prentki M, Matschinsky FM, Madiraju SR. Metabolic signaling in fuel-induced insulin secretion. Cell Metab. 2013; 18(2): 162–185.
- Robertson RP, Harmon J, Tran PO, et al. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes. 2003; 52(3): 581–587.
- Kitamura T, Ido Kitamura Y. Role of FoxO Proteins in Pancreatic beta Cells. Endocr J. 2007; 54(4): 507–515.
- Zhang T, Kim DH, Xiao X, et al. FoxO1 Plays an Important Role in Regulating β-Cell Compensation for Insulin Resistance in Male Mice. Endocrinology. 2016; 157(3): 1055–1070.
- Bouchi R, Foo KS, Hua H, et al. FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures. Nat Commun. 2014; 5: 4242.
- Bowker-Kinley MM, Davis WI, Wu P, et al. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 1998; 329 ( Pt 1): 191–196.
- Constantin-Teodosiu D, Constantin D, Stephens F, et al. The role of FOXO and PPAR transcription factors in diet-mediated inhibition of PDC activation and carbohydrate oxidation during exercise in humans and the role of pharmacological activation of PDC in overriding these changes. Diabetes. 2012; 61(5): 1017–1024.
- Rauramaa R, Kuusela P, Hietanen E. Adipose, muscle and lung tissue lipoprotein lipase activities in young streptozotocin treated rats. Horm Metab Res. 1980; 12(11): 591–595.
- Lin J, Wu H, Tarr PT, et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature. 2002; 418(6899): 797–801.
- Chung SY, Huang WC, Su CW, et al. FoxO6 and PGC-1α form a regulatory loop in myogenic cells. Biosci Rep. 2013; 33(3).
- Kamei Y, Mizukami J, Miura S, et al. A forkhead transcription factor FKHR up-regulates lipoprotein lipase expression in skeletal muscle. FEBS Letters. 2003; 536(1-3): 232–236.
- O'Neill BT, Bhardwaj G, Penniman CM, et al. FoxO transcription factors are critical regulators of diabetes-related muscle atrophy. Diabetes. 2019; 68(3): 556–570.
- Furuyama T, Kitayama K, Yamashita H, et al. Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J. 2003; 375(Pt 2): 365–371.
- Bastie CC, Nahlé Z, McLoughlin T, et al. FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms. J Biol Chem. 2005; 280(14): 14222–14229.
- Tsuchiya K, Ogawa Y. Forkhead box class O family member proteins: The biology and pathophysiological roles in diabetes. J Diabetes Investig. 2017; 8(6): 726–734.
- Tsuchiya K, Tanaka J, Shuiqing Yu, et al. FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis. Cell Metab. 2012; 15(3): 372–381.
- Federici M, Pandolfi A, De Filippis EA, et al. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation. 2004; 109(3): 399–405.
- Potente M, Urbich C, Sasaki Ki, et al. Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest. 2005; 115(9): 2382–2392.
- Tanaka J, Qiang Li, Banks AS, et al. Foxo1 links hyperglycemia to LDL oxidation and endothelial nitric oxide synthase dysfunction in vascular endothelial cells. Diabetes. 2009; 58(10): 2344–2354.
- Karki S, Farb MG, Ngo DTM, et al. Forkhead box O-1 modulation improves endothelial insulin resistance in human obesity. Arterioscler Thromb Vasc Biol. 2015; 35(6): 1498–1506.
- Menghini R, Casagrande V, Cardellini M, et al. FoxO1 regulates asymmetric dimethylarginine via downregulation of dimethylaminohydrolase 1 in human endothelial cells and subjects with atherosclerosis. Atherosclerosis. 2015; 242(1): 230–235.
- Nwadozi E, Roudier E, Rullman E, et al. Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high-fat diet. FASEB J. 2016; 30(9): 3039–3052.
- Tsuchiya K, Accili D. Liver sinusoidal endothelial cells link hyperinsulinemia to hepatic insulin resistance. Diabetes. 2013; 62(5): 1478–1489.
- Chung S, Ranjan R, Lee YG, et al. Distinct role of FoxO1 in M-CSF- and GM-CSF-differentiated macrophages contributes LPS-mediated IL-10: implication in hyperglycemia. J Leukoc Biol. 2015; 97(2): 327–339.
- Fan W, Morinaga H, Kim JJ, et al. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 2010; 29(24): 4223–4236.
- Wang Yu, Zhou Y, Graves DT. FOXO transcription factors: their clinical significance and regulation. Biomed Res Int. 2014; 2014: 925350.
- Lee S, Dong HH. FoxO integration of insulin signaling with glucose and lipid metabolism. J Endocrinol. 2017; 233(2): R67–R79.
- van der Horst A, Burgering BMT. Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol. 2007; 8(6): 440–450.
- Xie Qi, Chen J, Yuan Z. Post-translational regulation of FOXO. Acta Biochim Biophys Sin (Shanghai). 2012; 44(11): 897–901.
- Greer EL, Oskoui PR, Banko MR, et al. The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem. 2007; 282(41): 30107–30119.
- Essers MAG, Weijzen S, de Vries-Smits AMM, et al. FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J. 2004; 23(24): 4802–4812.
- Sunayama J, Tsuruta F, Masuyama N, et al. JNK antagonizes Akt-mediated survival signals by phosphorylating 14-3-3. J Cell Biol. 2005; 170(2): 295–304.
- Lehtinen MK, Yuan Z, Boag PR, et al. A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell. 2006; 125(5): 987–1001.
- Graves JD, Draves KE, Gotoh Y, et al. Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J. 1998; 17(8): 2224–2234.