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The role of FoxO in the regulation of metabolism

Abstract

Forkhead proteins, and FoxO1 in particular, play a significant role in regulating whole body energy metabolism. Glucose homeostasis is achieved by adjusting endogenous glucose production as well as glucose uptake by peripheral tissues in response to insulin. In the fasted state, the liver is primarily responsible for maintaining glucose levels, with FoxO1 playing a key role in promoting the expression of gluconeogenic enzymes. Following feeding, pancreatic beta cells secrete insulin, which promotes the uptake of glucose by peripheral tissues including skeletal muscle and adipose tissue, and can in part suppress gluconeogenic enzyme expression in the liver. In addition to directly regulating metabolism, FoxO1 also plays a role in the formation of both adipose tissue and skeletal muscle, two major organs that are critical for maintaining energy homeostasis. The importance of FoxO1 in energy homeostasis is particularly striking under conditions of metabolic dysfunction or insulin resistance. In obese or diabetic states, FoxO1-dependent gene expression promotes some of the deleterious characteristics associated with these conditions, including hyperglycemia and glucose intolerance. In addition, the increase in pancreatic beta cell mass that normally occurs in response to a rise in insulin demand is blunted by nuclear FoxO1 expression. However, under these same pathophysiological conditions, FoxO1 expression may help drive the expression of genes involved in combating oxidative stress, thereby preserving cellular function. FoxO1 may also be involved in promoting the switch from carbohydrate to fatty acid as the major energy source during starvation.

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References

  • Accili D, Arden KC . (2004). FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117: 421–426.

    Article  CAS  PubMed  Google Scholar 

  • Accili D, Drago J, Lee EJ, Johnson MD, Cool MH, Salvatore P et al. (1996). Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat Genet 12: 106–109.

    Article  CAS  PubMed  Google Scholar 

  • Accili D, Taylor SI . (1991). Targeted inactivation of the insulin receptor gene in mouse 3T3-L1 fibroblasts via homologous recombination. Proc Natl Acad Sci USA 88: 4708–4712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahima RS, Flier JS . (2000). Adipose tissue as an endocrine organ. Trends Endocrinol Metab 11: 327–332.

    Article  CAS  PubMed  Google Scholar 

  • Alberti KG, Zimmet P, Shaw J . (2006). Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 23: 469–480.

    Article  CAS  PubMed  Google Scholar 

  • Allen DL, Unterman TG . (2007). Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors. Am J Physiol Cell Physiol 292: C188–C199.

    Article  CAS  PubMed  Google Scholar 

  • Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Meseck M et al. (2004). Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest 114: 1493–1503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN et al. (2003). Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Am J Physiol Endocrinol Metab 285: E718–E728.

    Article  CAS  PubMed  Google Scholar 

  • Araki E, Lipes MA, Patti ME, Bruning JC, Haag III B, Johnson RS et al. (1994). Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372: 186–190.

    Article  CAS  PubMed  Google Scholar 

  • Armoni M, Harel C, Karni S, Chen H, Bar-Yoseph F, Ver MR et al. (2006). FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity. J Biol Chem 281: 19881–19891.

    Article  CAS  PubMed  Google Scholar 

  • Bai L, Pang WJ, Yang YJ, Yang GS . (2007). Modulation of Sirt1 by resveratrol and nicotinamide alters proliferation and differentiation of pig preadipocytes. Mol Cell Biochem 307: 129–140.

    Article  PubMed  CAS  Google Scholar 

  • Barthel A, Schmoll D, Kruger KD, Bahrenberg G, Walther R, Roth RA et al. (2001). Differential regulation of endogenous glucose-6-phosphatase and phosphoenolpyruvate carboxykinase gene expression by the forkhead transcription factor FKHR in H4IIE-hepatoma cells. Biochem Biophys Res Commun 285: 897–902.

    Article  CAS  PubMed  Google Scholar 

  • Bastie CC, Nahle Z, McLoughlin T, Esser K, Zhang W, Unterman T et al. (2005). FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms. J Biol Chem 280: 14222–14229.

    Article  CAS  PubMed  Google Scholar 

  • Baudry A, Yang ZZ, Hemmings BA . (2006). PKBalpha is required for adipose differentiation of mouse embryonic fibroblasts. J Cell Sci 119: 889–897.

    Article  CAS  PubMed  Google Scholar 

  • Ben-Shushan E, Marshak S, Shoshkes M, Cerasi E, Melloul D . (2001). A pancreatic beta-cell-specific enhancer in the human PDX-1 gene is regulated by hepatocyte nuclear factor 3beta (HNF-3beta), HNF-1alpha, and SPs transcription factors. J Biol Chem 276: 17533–17540.

    Article  CAS  PubMed  Google Scholar 

  • Beqaj S, Jakkaraju S, Mattingly RR, Pan D, Schuger L . (2002). High RhoA activity maintains the undifferentiated mesenchymal cell phenotype, whereas RhoA down-regulation by laminin-2 induces smooth muscle myogenesis. J Cell Biol 156: 893–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biggs III WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC . (1999). Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 96: 7421–7426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA et al. (2001). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294: 1704–1708.

    Article  CAS  PubMed  Google Scholar 

  • Bois PR, Grosveld GC . (2003). FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts. EMBO J 22: 1147–1157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouwens L, Rooman I . (2005). Regulation of pancreatic beta-cell mass. Physiol Rev 85: 1255–1270.

    Article  CAS  PubMed  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96: 857–868.

    Article  CAS  PubMed  Google Scholar 

  • Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR . (1997). Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88: 561–572.

    Article  CAS  PubMed  Google Scholar 

  • Burgering BM, Kops GJ . (2002). Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27: 352–360.

    Article  CAS  PubMed  Google Scholar 

  • Buteau J, Roduit R, Susini S, Prentki M . (1999). Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells. Diabetologia 42: 856–864.

    Article  CAS  PubMed  Google Scholar 

  • Buteau J, Spatz ML, Accili D . (2006). Transcription factor FoxO1 mediates glucagon-like peptide-1 effects on pancreatic beta-cell mass. Diabetes 55: 1190–1196.

    Article  CAS  PubMed  Google Scholar 

  • Chen PL, Riley DJ, Chen Y, Lee WH . (1996). Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs. Genes Dev 10: 2794–2804.

    Article  CAS  PubMed  Google Scholar 

  • Coburn CT, Knapp Jr FF, Febbraio M, Beets AL, Silverstein RL, Abumrad NA . (2000). Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice. J Biol Chem 275: 32523–32529.

    Article  CAS  PubMed  Google Scholar 

  • Conejo R, de Alvaro C, Benito M, Cuadrado A, Lorenzo M . (2002). Insulin restores differentiation of Ras-transformed C2C12 myoblasts by inducing NF-kappaB through an AKT/P70S6K/p38-MAPK pathway. Oncogene 21: 3739–3753.

    Article  CAS  PubMed  Google Scholar 

  • Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR . (1997). The mitogenic and myogenic actions of insulin-like growth factors utilize distinct signaling pathways. J Biol Chem 272: 6653–6662.

    Article  CAS  PubMed  Google Scholar 

  • Cuenda A, Cohen P . (1999). Stress-activated protein kinase-2/p38 and a rapamycin-sensitive pathway are required for C2C12 myogenesis. J Biol Chem 274: 4341–4346.

    Article  CAS  PubMed  Google Scholar 

  • Daitoku H, Yamagata K, Matsuzaki H, Hatta M, Fukamizu A . (2003). Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes 52: 642–649.

    Article  CAS  PubMed  Google Scholar 

  • de Lange P, Moreno M, Silvestri E, Lombardi A, Goglia F, Lanni A . (2007). Fuel economy in food-deprived skeletal muscle: signaling pathways and regulatory mechanisms. FASEB J 21: 3431–3441.

    Article  CAS  PubMed  Google Scholar 

  • Dong X, Park S, Lin X, Copps K, Yi X, White MF . (2006). Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest 116: 101–114.

    Article  CAS  PubMed  Google Scholar 

  • Dowell P, Otto TC, Adi S, Lane MD . (2003). Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem 278: 45485–45491.

    Article  CAS  PubMed  Google Scholar 

  • Du K, Herzig S, Kulkarni RN, Montminy M . (2003). TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300: 1574–1577.

    Article  CAS  PubMed  Google Scholar 

  • Duivenvoorden I, Teusink B, Rensen PC, Romijn JA, Havekes LM, Voshol PJ . (2005). Apolipoprotein C3 deficiency results in diet-induced obesity and aggravated insulin resistance in mice. Diabetes 54: 664–671.

    Article  CAS  PubMed  Google Scholar 

  • Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F . (2004). SREBP transcription factors: master regulators of lipid homeostasis. Biochimie 86: 839–848.

    Article  CAS  PubMed  Google Scholar 

  • Erbay E, Chen J . (2001). The mammalian target of rapamycin regulates C2C12 myogenesis via a kinase-independent mechanism. J Biol Chem 276: 36079–36082.

    Article  CAS  PubMed  Google Scholar 

  • Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL et al. (2004). FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23: 4802–4812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fajas L, Landsberg RL, Huss-Garcia Y, Sardet C, Lees JA, Auwerx J . (2002). E2Fs regulate adipocyte differentiation. Dev Cell 3: 39–49.

    Article  CAS  PubMed  Google Scholar 

  • Farmer SR . (2005). Regulation of PPARgamma activity during adipogenesis. Int J Obes (Lond) 29 (Suppl 1): S13–S16.

    Article  CAS  Google Scholar 

  • Foretz M, Guichard C, Ferre P, Foufelle F . (1999). Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci USA 96: 12737–12742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freemark M, Avril I, Fleenor D, Driscoll P, Petro A, Opara E et al. (2002). Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance. Endocrinology 143: 1378–1385.

    Article  CAS  PubMed  Google Scholar 

  • Frescas D, Valenti L, Accili D . (2005). Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280: 20589–20595.

    Article  CAS  PubMed  Google Scholar 

  • Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y et al. (2004). Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114: 1752–1761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furukawa-Hibi Y, Kobayashi Y, Chen C, Motoyama N . (2005). FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxid Redox Signal 7: 752–760.

    Article  CAS  PubMed  Google Scholar 

  • Furuyama T, Kitayama K, Yamashita H, Mori N . (2003). Forkhead transcription factor FOXO1 (FKHR)-dependent induction of PDK4 gene expression in skeletal muscle during energy deprivation. Biochem J 375: 365–371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher III FJ, Emanuel BS et al. (1993). Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 5: 230–235.

    Article  CAS  PubMed  Google Scholar 

  • Gan L, Han Y, Bastianetto S, Dumont Y, Unterman TG, Quirion R . (2005). FoxO-dependent and -independent mechanisms mediate SirT1 effects on IGFBP-1 gene expression. Biochem Biophys Res Commun 337: 1092–1096.

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Ocana A, Takane KK, Syed MA, Philbrick WM, Vasavada RC, Stewart AF . (2000). Hepatocyte growth factor overexpression in the islet of transgenic mice increases beta cell proliferation, enhances islet mass, and induces mild hypoglycemia. J Biol Chem 275: 1226–1232.

    Article  CAS  PubMed  Google Scholar 

  • Glass DJ . (2003). Signalling pathways that mediate skeletal muscle hypertrophy and atrophy. Nat Cell Biol 5: 87–90.

    Article  CAS  PubMed  Google Scholar 

  • Glauser DA, Schlegel W . (2007). The emerging role of FOXO transcription factors in pancreatic beta cells. J Endocrinol 193: 195–207.

    Article  CAS  PubMed  Google Scholar 

  • Gleason CE, Gross DN, Birnbaum MJ . (2007). When the usual insulin is just not enough. Proc Natl Acad Sci USA 104: 8681–8682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goldberg IJ . (1996). Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J Lipid Res 37: 693–707.

    CAS  PubMed  Google Scholar 

  • Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL . (2001). Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA 98: 14440–14445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzalez GA, Montminy MR . (1989). Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59: 675–680.

    Article  CAS  PubMed  Google Scholar 

  • Grankvist K, Marklund SL, Taljedal IB . (1981). CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 199: 393–398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greer EL, Brunet A . (2005). FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24: 7410–7425.

    Article  CAS  PubMed  Google Scholar 

  • Greiwe JS, Holloszy JO, Semenkovich CF . (2000). Exercise induces lipoprotein lipase and GLUT-4 protein in muscle independent of adrenergic-receptor signaling. J Appl Physiol 89: 176–181.

    Article  CAS  PubMed  Google Scholar 

  • Grill V, Bjorklund A . (2001). Overstimulation and beta-cell function. Diabetes 50 (Suppl 1): S122–S124.

    Article  CAS  PubMed  Google Scholar 

  • Hajri T, Abumrad NA . (2002). Fatty acid transport across membranes: relevance to nutrition and metabolic pathology. Annu Rev Nutr 22: 383–415.

    Article  CAS  PubMed  Google Scholar 

  • Hajri T, Han XX, Bonen A, Abumrad NA . (2002). Defective fatty acid uptake modulates insulin responsiveness and metabolic responses to diet in CD36-null mice. J Clin Invest 109: 1381–1389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hall RK, Yamasaki T, Kucera T, Waltner-Law M, O'Brien R, Granner DK . (2000). Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins. J Biol Chem 275: 30169–30175.

    Article  CAS  PubMed  Google Scholar 

  • Hansmannel F, Mordier S, Iynedjian PB . (2006). Insulin induction of glucokinase and fatty acid synthase in hepatocytes: analysis of the roles of sterol-regulatory-element-binding protein-1c and liver X receptor. Biochem J 399: 275–283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A et al. (2001). CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413: 179–183.

    Article  CAS  PubMed  Google Scholar 

  • Hirota K, Daitoku H, Matsuzaki H, Araya N, Yamagata K, Asada S et al. (2003). Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor. J Biol Chem 278: 13056–13060.

    Article  CAS  PubMed  Google Scholar 

  • Holz GG, Chepurny OG . (2005). Diabetes outfoxed by GLP-1? Sci STKE 2005: pe2.

    PubMed  PubMed Central  Google Scholar 

  • Hribal ML, Nakae J, Kitamura T, Shutter JR, Accili D . (2003). Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors. J Cell Biol 162: 535–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang B, Wu P, Bowker-Kinley MM, Harris RA . (2002). Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 51: 276–283.

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Iida KT, Sone H, Ajisaka R . (2007). The regulation of adiponectin receptors expression by acute exercise in mice. Exp Clin Endocrinol Diabetes 115: 417–422.

    Article  CAS  PubMed  Google Scholar 

  • Imae M, Fu Z, Yoshida A, Noguchi T, Kato H . (2003). Nutritional and hormonal factors control the gene expression of FoxOs, the mammalian homologues of DAF-16. J Mol Endocrinol 30: 253–262.

    Article  CAS  PubMed  Google Scholar 

  • Ito Y, Azrolan N, O'Connell A, Walsh A, Breslow JL . (1990). Hypertriglyceridemia as a result of human apo CIII gene expression in transgenic mice. Science 249: 790–793.

    Article  CAS  PubMed  Google Scholar 

  • Jackerott M, Moldrup A, Thams P, Galsgaard ED, Knudsen J, Lee YC et al. (2006). STAT5 activity in pancreatic beta-cells influences the severity of diabetes in animal models of type 1 and 2 diabetes. Diabetes 55: 2705–2712.

    Article  CAS  PubMed  Google Scholar 

  • Jagoe RT, Goldberg AL . (2001). What do we really know about the ubiquitin–proteasome pathway in muscle atrophy? Curr Opin Clin Nutr Metab Care 4: 183–190.

    Article  CAS  PubMed  Google Scholar 

  • Jiang BH, Aoki M, Zheng JZ, Li J, Vogt PK . (1999). Myogenic signaling of phosphatidylinositol 3-kinase requires the serine-threonine kinase Akt/protein kinase B. Proc Natl Acad Sci USA 96: 2077–2081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang BH, Zheng JZ, Vogt PK . (1998). An essential role of phosphatidylinositol 3-kinase in myogenic differentiation. Proc Natl Acad Sci USA 95: 14179–14183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jing E, Gesta S, Kahn CR . (2007). SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab 6: 105–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R et al. (2002). Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277: 11019–11025.

    Article  CAS  PubMed  Google Scholar 

  • Joshi RL, Lamothe B, Cordonnier N, Mesbah K, Monthioux E, Jami J et al. (1996). Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. EMBO J 15: 1542–1547.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaeberlein M, McVey M, Guarente L . (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13: 2570–2580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaliman P, Canicio J, Shepherd PR, Beeton CA, Testar X, Palacin M et al. (1998). Insulin-like growth factors require phosphatidylinositol 3-kinase to signal myogenesis: dominant negative p85 expression blocks differentiation of L6E9 muscle cells. Mol Endocrinol 12: 66–77.

    Article  CAS  PubMed  Google Scholar 

  • Kamei Y, Miura S, Suzuki M, Kai Y, Mizukami J, Taniguchi T et al. (2004). 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 279: 41114–41123.

    Article  CAS  PubMed  Google Scholar 

  • Kamei Y, Mizukami J, Miura S, Suzuki M, Takahashi N, Kawada T et al. (2003). A forkhead transcription factor FKHR up-regulates lipoprotein lipase expression in skeletal muscle. FEBS Lett 536: 232–236.

    Article  CAS  PubMed  Google Scholar 

  • Kaneto H, Miyatsuka T, Shiraiwa T, Yamamoto K, Kato K, Fujitani Y et al. (2007). Crucial role of PDX-1 in pancreas development, beta-cell differentiation, and induction of surrogate beta-cells. Curr Med Chem 14: 1745–1752.

    Article  CAS  PubMed  Google Scholar 

  • Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC . (2002). Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem 277: 30010–30018.

    Article  CAS  PubMed  Google Scholar 

  • Katz J, McGarry JD . (1984). The glucose paradox. Is glucose a substrate for liver metabolism? J Clin Invest 74: 1901–1909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawamori D, Kajimoto Y, Kaneto H, Umayahara Y, Fujitani Y, Miyatsuka T et al. (2003). Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase. Diabetes 52: 2896–2904.

    Article  CAS  PubMed  Google Scholar 

  • Kawamori D, Kaneto H, Nakatani Y, Matsuoka TA, Matsuhisa M, Hori M et al. (2006). The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem 281: 1091–1098.

    Article  CAS  PubMed  Google Scholar 

  • Kido Y, Burks DJ, Withers D, Bruning JC, Kahn CR, White MF et al. (2000). Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest 105: 199–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim SJ, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh CH . (2005). Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression. J Biol Chem 280: 22297–22307.

    Article  CAS  PubMed  Google Scholar 

  • Kim SY, Kim HI, Kim TH, Im SS, Park SK, Lee IK et al. (2004). SREBP-1c mediates the insulin-dependent hepatic glucokinase expression. J Biol Chem 279: 30823–30829.

    Article  CAS  PubMed  Google Scholar 

  • Kitamura T, Ido Kitamura Y . (2007). Role of FoxO proteins in pancreatic beta cells. Endocr J 54: 507–515.

    Article  CAS  PubMed  Google Scholar 

  • Kitamura T, Kitamura YI, Funahashi Y, Shawber CJ, Castrillon DH, Kollipara R et al. (2007). A Foxo/Notch pathway controls myogenic differentiation and fiber type specification. J Clin Invest 117: 2477–2485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kitamura T, Nakae J, Kitamura Y, Kido Y, Biggs III WH, Wright CV et al. (2002). The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth. J Clin Invest 110: 1839–1847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kitamura YI, Kitamura T, Kruse JP, Raum JC, Stein R, Gu W et al. (2005). FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction. Cell Metab 2: 153–163.

    Article  CAS  PubMed  Google Scholar 

  • Kubota N, Tobe K, Terauchi Y, Eto K, Yamauchi T, Suzuki R et al. (2000). Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. Diabetes 49: 1880–1889.

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR . (1999). Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96: 329–339.

    Article  CAS  PubMed  Google Scholar 

  • Kulkarni RN, Holzenberger M, Shih DQ, Ozcan U, Stoffel M, Magnuson MA et al. (2002). beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet 31: 111–115.

    Article  CAS  PubMed  Google Scholar 

  • Kuriyama H, Shimomura I, Kishida K, Kondo H, Furuyama N, Nishizawa H et al. (2002). Coordinated regulation of fat-specific and liver-specific glycerol channels, aquaporin adipose and aquaporin 9. Diabetes 51: 2915–2921.

    Article  CAS  PubMed  Google Scholar 

  • Kushner JA, Simpson L, Wartschow LM, Guo S, Rankin MM, Parsons R et al. (2005). Phosphatase and tensin homolog regulation of islet growth and glucose homeostasis. J Biol Chem 280: 39388–39393.

    Article  CAS  PubMed  Google Scholar 

  • Kushner JA, Ye J, Schubert M, Burks DJ, Dow MA, Flint CL et al. (2002). Pdx1 restores beta cell function in Irs2 knockout mice. J Clin Invest 109: 1193–1201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon HS, Huang B, Unterman TG, Harris RA . (2004). Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Diabetes 53: 899–910.

    Article  CAS  PubMed  Google Scholar 

  • Ladu MJ, Kapsas H, Palmer WK . (1991). Regulation of lipoprotein lipase in adipose and muscle tissues during fasting. Am J Physiol 260: R953–R959.

    CAS  PubMed  Google Scholar 

  • Lantz KA, Kaestner KH . (2005). Winged-helix transcription factors and pancreatic development. Clin Sci (Lond) 108: 195–204.

    Article  CAS  Google Scholar 

  • Large V, Peroni O, Letexier D, Ray H, Beylot M . (2004). Metabolism of lipids in human white adipocyte. Diabetes Metab 30: 294–309.

    Article  CAS  PubMed  Google Scholar 

  • Lecker SH, Jagoe RT, Gilbert A, Gomes M, Baracos V, Bailey J et al. (2004). Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J 18: 39–51.

    Article  CAS  PubMed  Google Scholar 

  • Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM et al. (2006). PPARdelta regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci USA 103: 3444–3449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee CS, Sund NJ, Vatamaniuk MZ, Matschinsky FM, Stoffers DA, Kaestner KH . (2002). Foxa2 controls Pdx1 gene expression in pancreatic beta-cells in vivo. Diabetes 51: 2546–2551.

    Article  CAS  PubMed  Google Scholar 

  • Lee SW, Dai G, Hu Z, Wang X, Du J, Mitch WE . (2004). Regulation of muscle protein degradation: coordinated control of apoptotic and ubiquitin–proteasome systems by phosphatidylinositol 3 kinase. J Am Soc Nephrol 15: 1537–1545.

    Article  CAS  PubMed  Google Scholar 

  • Lefebvre P, Chinetti G, Fruchart JC, Staels B . (2006). Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116: 571–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leger B, Cartoni R, Praz M, Lamon S, Deriaz O, Crettenand A et al. (2006a). Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy. J Physiol 576: 923–933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leger B, Vergani L, Soraru G, Hespel P, Derave W, Gobelet C et al. (2006b). Human skeletal muscle atrophy in amyotrophic lateral sclerosis reveals a reduction in Akt and an increase in atrogin-1. FASEB J 20: 583–585.

    Article  CAS  PubMed  Google Scholar 

  • Li X, Monks B, Ge Q, Birnbaum MJ . (2007). Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 447: 1012–1016.

    Article  CAS  PubMed  Google Scholar 

  • Lindberg K, Ronn SG, Tornehave D, Richter H, Hansen JA, Romer J et al. (2005). Regulation of pancreatic beta-cell mass and proliferation by SOCS-3. J Mol Endocrinol 35: 231–243.

    Article  CAS  PubMed  Google Scholar 

  • Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rassoulzadegan M et al. (2003). Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J 17: 2299–2301.

    Article  CAS  PubMed  Google Scholar 

  • Mandrup S, Lane MD . (1997). Regulating adipogenesis. J Biol Chem 272: 5367–5370.

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M, Han S, Kitamura T, Accili D . (2006). Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 116: 2464–2472.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D . (2007). Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor foxo1 in liver. Cell Metab 6: 208–216.

    Article  CAS  PubMed  Google Scholar 

  • McKinsey TA, Zhang CL, Olson EN . (2002). Signaling chromatin to make muscle. Curr Opin Cell Biol 14: 763–772.

    Article  CAS  PubMed  Google Scholar 

  • McPherron AC, Lawler AM, Lee SJ . (1997). Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387: 83–90.

    Article  CAS  PubMed  Google Scholar 

  • Meriane M, Roux P, Primig M, Fort P, Gauthier-Rouviere C . (2000). Critical activities of Rac1 and Cdc42Hs in skeletal myogenesis: antagonistic effects of JNK and p38 pathways. Mol Biol Cell 11: 2513–2528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miki H, Yamauchi T, Suzuki R, Komeda K, Tsuchida A, Kubota N et al. (2001). Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Mol Cell Biol 21: 2521–2532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morrison RF, Farmer SR . (1999). Role of PPARgamma in regulating a cascade expression of cyclin-dependent kinase inhibitors, p18(INK4c) and p21(Waf1/Cip1), during adipogenesis. J Biol Chem 274: 17088–17097.

    Article  CAS  PubMed  Google Scholar 

  • Morrison RF, Farmer SR . (2000). Hormonal signaling and transcriptional control of adipocyte differentiation. J Nutr 130: 3116S–3121S.

    Article  CAS  PubMed  Google Scholar 

  • Mounier C, Dumas V, Posner BI . (2006). Regulation of hepatic insulin-like growth factor-binding protein-1 gene expression by insulin: central role for mammalian target of rapamycin independent of forkhead box O proteins. Endocrinology 147: 2383–2391.

    Article  CAS  PubMed  Google Scholar 

  • Murtaugh LC . (2007). Pancreas and beta-cell development: from the actual to the possible. Development 134: 427–438.

    Article  CAS  PubMed  Google Scholar 

  • Naimi M, Gautier N, Chaussade C, Valverde AM, Accili D, Van Obberghen E . (2007). Nuclear forkhead box O1 controls and integrates key signaling pathways in hepatocytes. Endocrinology 148: 2424–2434.

    Article  CAS  PubMed  Google Scholar 

  • Nakae J, Biggs III WH, Kitamura T, Cavenee WK, Wright CV, Arden KC et al. (2002). Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 32: 245–253.

    Article  CAS  PubMed  Google Scholar 

  • Nakae J, Cao Y, Daitoku H, Fukamizu A, Ogawa W, Yano Y et al. (2006). The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. J Clin Invest 116: 2473–2483.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakae J, Kitamura T, Kitamura Y, Biggs III WH, Arden KC, Accili D . (2003). The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell 4: 119–129.

    Article  CAS  PubMed  Google Scholar 

  • Newgard CB, McGarry JD . (1995). Metabolic coupling factors in pancreatic beta-cell signal transduction. Annu Rev Biochem 64: 689–719.

    Article  CAS  PubMed  Google Scholar 

  • Nishiyama T, Kii I, Kudo A . (2004). Inactivation of Rho/ROCK signaling is crucial for the nuclear accumulation of FKHR and myoblast fusion. J Biol Chem 279: 47311–47319.

    Article  CAS  PubMed  Google Scholar 

  • Okada T, Liew CW, Hu J, Hinault C, Michael MD, Krtzfeldt J et al. (2007). Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance. Proc Natl Acad Sci USA 104: 8977–8982.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park S, Dong X, Fisher TL, Dunn S, Omer AK, Weir G et al. (2006). Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem 281: 1159–1168.

    Article  CAS  PubMed  Google Scholar 

  • Peters SJ, Harris RA, Wu P, Pehleman TL, Heigenhauser GJ, Spriet LL . (2001). Human skeletal muscle PDH kinase activity and isoform expression during a 3-day high-fat/low-carbohydrate diet. Am J Physiol Endocrinol Metab 281: E1151–E1158.

    Article  CAS  PubMed  Google Scholar 

  • Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R et al. (2004). Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429: 771–776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pilegaard H, Ordway GA, Saltin B, Neufer PD . (2000). Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. Am J Physiol Endocrinol Metab 279: E806–E814.

    Article  CAS  PubMed  Google Scholar 

  • Pilegaard H, Saltin B, Neufer PD . (2003). Effect of short-term fasting and refeeding on transcriptional regulation of metabolic genes in human skeletal muscle. Diabetes 52: 657–662.

    Article  CAS  PubMed  Google Scholar 

  • Poitout V, Robertson RP . (2002). Minireview: secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity. Endocrinology 143: 339–342.

    Article  CAS  PubMed  Google Scholar 

  • Postic C, Dentin R, Girard J . (2004). Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab 30: 398–408.

    Article  CAS  PubMed  Google Scholar 

  • Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sussel L . (2004). Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA 101: 2924–2929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F et al. (2003). Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1alpha interaction. Nature 423: 550–555.

    Article  CAS  PubMed  Google Scholar 

  • Qu S, Altomonte J, Perdomo G, He J, Fan Y, Kamagate A et al. (2006). Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism. Endocrinology 147: 5641–5652.

    Article  CAS  PubMed  Google Scholar 

  • Qu S, Su D, Altomonte J, Kamagate A, He J, Perdomo G et al. (2007). PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1. Am J Physiol Endocrinol Metab 292: E421–E434.

    Article  CAS  PubMed  Google Scholar 

  • Randle PJ . (1986). Fuel selection in animals. Biochem Soc Trans 14: 799–806.

    Article  CAS  PubMed  Google Scholar 

  • Rauramaa R, Kuusela P, Hietanen E . (1980). Adipose, muscle and lung tissue lipoprotein lipase activities in young streptozotocin treated rats. Horm Metab Res 12: 591–595.

    Article  CAS  PubMed  Google Scholar 

  • Reisz-Porszasz S, Bhasin S, Artaza JN, Shen R, Sinha-Hikim I, Hogue A et al. (2003). Lower skeletal muscle mass in male transgenic mice with muscle-specific overexpression of myostatin. Am J Physiol Endocrinol Metab 285: E876–E888.

    Article  CAS  PubMed  Google Scholar 

  • Rhee J, Inoue Y, Yoon JC, Puigserver P, Fan M, Gonzalez FJ et al. (2003). Regulation of hepatic fasting response by PPARgamma coactivator-1alpha (PGC-1): requirement for hepatocyte nuclear factor 4alpha in gluconeogenesis. Proc Natl Acad Sci USA 100: 4012–4017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ritzel RA, Hansen JB, Veldhuis JD, Butler PC . (2004). Induction of beta-cell rest by a Kir6.2/SUR1-selective K(ATP)-channel opener preserves beta-cell insulin stores and insulin secretion in human islets cultured at high (11 mM) glucose. J Clin Endocrinol Metab 89: 795–805.

    Article  CAS  PubMed  Google Scholar 

  • Robertson RP, Harmon J, Tran PO, Poitout V . (2004). Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes 53 (Suppl 1): S119–S124.

    Article  CAS  PubMed  Google Scholar 

  • Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P . (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113–118.

    Article  CAS  PubMed  Google Scholar 

  • Rosen ED, MacDougald OA . (2006). Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7: 885–896.

    Article  CAS  PubMed  Google Scholar 

  • Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS et al. (1999). PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4: 611–617.

    Article  CAS  PubMed  Google Scholar 

  • Rosen ED, Spiegelman BM . (2000). Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16: 145–171.

    Article  CAS  PubMed  Google Scholar 

  • Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM . (2000). Transcriptional regulation of adipogenesis. Genes Dev 14: 1293–1307.

    CAS  PubMed  Google Scholar 

  • Roth U, Curth K, Unterman TG, Kietzmann T . (2004). 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 279: 2623–2631.

    Article  CAS  PubMed  Google Scholar 

  • Sacheck JM, Hyatt JP, Raffaello A, Jagoe RT, Roy RR, Edgerton VR et al. (2007). Rapid disuse and denervation atrophy involve transcriptional changes similar to those of muscle wasting during systemic diseases. FASEB J 21: 140–155.

    Article  CAS  PubMed  Google Scholar 

  • Samuel VT, Choi CS, Phillips TG, Romanelli AJ, Geisler JG, Bhanot S et al. (2006). Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes 55: 2042–2050.

    Article  CAS  PubMed  Google Scholar 

  • Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A et al. (2004). Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 117: 399–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schilling MM, Oeser JK, Boustead JN, Flemming BP, O'Brien RM . (2006). Gluconeogenesis: re-evaluating the FOXO1–PGC-1alpha connection. Nature 443: E10–E11.

    Article  CAS  PubMed  Google Scholar 

  • Sekine K, Chen YR, Kojima N, Ogata K, Fukamizu A, Miyajima A . (2007). Foxo1 links insulin signaling to C/EBPalpha and regulates gluconeogenesis during liver development. EMBO J 26: 3607–3615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Southgate RJ, Bruce CR, Carey AL, Steinberg GR, Walder K, Monks R et al. (2005). PGC-1alpha gene expression is down-regulated by Akt-mediated phosphorylation and nuclear exclusion of FoxO1 in insulin-stimulated skeletal muscle. FASEB J 19: 2072–2074.

    Article  CAS  PubMed  Google Scholar 

  • Southgate RJ, Neill B, Prelovsek O, El-Osta A, Kamei Y, Miura S et al. (2007). FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. J Biol Chem 282: 21176–21186.

    Article  CAS  PubMed  Google Scholar 

  • Spriet LL, Tunstall RJ, Watt MJ, Mehan KA, Hargreaves M, Cameron-Smith D . (2004). Pyruvate dehydrogenase activation and kinase expression in human skeletal muscle during fasting. J Appl Physiol 96: 2082–2087.

    Article  CAS  PubMed  Google Scholar 

  • Stitt TN, Drujan D, Clarke BA, Panaro F, Timofeyva Y, Kline WO et al. (2004). The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Mol Cell 14: 395–403.

    Article  CAS  PubMed  Google Scholar 

  • Stoffers DA, Kieffer TJ, Hussain MA, Drucker DJ, Bonner-Weir S, Habener JF et al. (2000). Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49: 741–748.

    Article  CAS  PubMed  Google Scholar 

  • Straub SG, Sharp GW . (2002). Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab Res Rev 18: 451–463.

    Article  CAS  PubMed  Google Scholar 

  • Subauste AR, Burant CF . (2007). Role of FoxO1 in FFA-induced oxidative stress in adipocytes. Am J Physiol Endocrinol Metab 293: E159–E164.

    Article  CAS  PubMed  Google Scholar 

  • Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T et al (1994). Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372: 182–186.

    Article  CAS  PubMed  Google Scholar 

  • Tang ED, Nunez G, Barr FG, Guan KL . (1999). Negative regulation of the forkhead transcription factor FKHR by Akt. J Biol Chem 274: 16741–16746.

    Article  CAS  PubMed  Google Scholar 

  • Tang QQ, Otto TC, Lane MD . (2003). Mitotic clonal expansion: a synchronous process required for adipogenesis. Proc Natl Acad Sci USA 100: 44–49.

    Article  CAS  PubMed  Google Scholar 

  • Tiedge M, Lortz S, Munday R, Lenzen S . (1998). Complementary action of antioxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against the toxicity of reactive oxygen species. Diabetes 47: 1578–1585.

    Article  CAS  PubMed  Google Scholar 

  • Tissenbaum HA, Guarente L . (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410: 227–230.

    Article  CAS  PubMed  Google Scholar 

  • Tobin KA, Ulven SM, Schuster GU, Steineger HH, Andresen SM, Gustafsson JA et al. (2002). Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J Biol Chem 277: 10691–10697.

    Article  CAS  PubMed  Google Scholar 

  • Tseng YH, Kriauciunas KM, Kokkotou E, Kahn CR . (2004). Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol Cell Biol 24: 1918–1929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsintzas K, Jewell K, Kamran M, Laithwaite D, Boonsong T, Littlewood J et al. (2006). Differential regulation of metabolic genes in skeletal muscle during starvation and refeeding in humans. J Physiol 575: 291–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuchida A, Yamauchi T, Ito Y, Hada Y, Maki T, Takekawa S et al. (2004). Insulin/Foxo1 pathway regulates expression levels of adiponectin receptors and adiponectin sensitivity. J Biol Chem 279: 30817–30822.

    Article  CAS  PubMed  Google Scholar 

  • Tureckova J, Wilson EM, Cappalonga JL, Rotwein P . (2001). Insulin-like growth factor-mediated muscle differentiation: collaboration between phosphatidylinositol 3-kinase–Akt-signaling pathways and myogenin. J Biol Chem 276: 39264–39270.

    Article  CAS  PubMed  Google Scholar 

  • Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD et al. (1995). Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269: 1108–1112.

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Cahill CM, Pineyro MA, Zhou J, Doyle ME, Egan JM . (1999). Glucagon-like peptide-1 regulates the beta cell transcription factor, PDX-1, in insulinoma cells. Endocrinology 140: 4904–4907.

    Article  CAS  PubMed  Google Scholar 

  • Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H et al. (2003). Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113: 159–170.

    Article  CAS  PubMed  Google Scholar 

  • Wilson EM, Rotwein P . (2007). Selective control of skeletal muscle differentiation by Akt1. J Biol Chem 282: 5106–5110.

    Article  CAS  PubMed  Google Scholar 

  • Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S et al. (1998). Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391: 900–904.

    Article  CAS  PubMed  Google Scholar 

  • Wu KL, Gannon M, Peshavaria M, Offield MF, Henderson E, Ray M et al. (1997). Hepatocyte nuclear factor 3beta is involved in pancreatic beta-cell-specific transcription of the pdx-1 gene. Mol Cell Biol 17: 6002–6013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM, Harris RA . (1998). Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem J 329 (Part 1): 197–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu Z, Bucher NL, Farmer SR . (1996). Induction of peroxisome proliferator-activated receptor gamma during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPbeta, C/EBPdelta, and glucocorticoids. Mol Cell Biol 16: 4128–4136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu J, Liao K . (2004). Protein kinase B/AKT 1 plays a pivotal role in insulin-like growth factor-1 receptor signaling induced 3T3-L1 adipocyte differentiation. J Biol Chem 279: 35914–35922.

    Article  CAS  PubMed  Google Scholar 

  • Yamauchi T, Tobe K, Tamemoto H, Ueki K, Kaburagi Y, Yamamoto-Honda R et al. (1996). Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol 16: 3074–3084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yeh WC, Cao Z, Classon M, McKnight SL . (1995). Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev 9: 168–181.

    Article  CAS  PubMed  Google Scholar 

  • Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J et al. (2001). Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413: 131–138.

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa H, Ma Z, Bjorklund A, Grill V . (2004). Short-term intermittent exposure to diazoxide improves functional performance of beta-cells in a high-glucose environment. Am J Physiol Endocrinol Metab 287: E1202–E1208.

    Article  CAS  PubMed  Google Scholar 

  • Zhang W, Patil S, Chauhan B, Guo S, Powell DR, Le J et al. (2006). FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression. J Biol Chem 281: 10105–10117.

    Article  CAS  PubMed  Google Scholar 

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Gross, D., van den Heuvel, A. & Birnbaum, M. The role of FoxO in the regulation of metabolism. Oncogene 27, 2320–2336 (2008). https://doi.org/10.1038/onc.2008.25

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