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• W2009010832 abstract "The hallmark of type 2 diabetes is excessive hepatic glucose production. Several transcription factors and coactivators regulate this process in cultured cells. But gene ablation experiments have yielded few clues as to the physiologic mediators of this process in vivo. We show that inactivation of the gene encoding forkhead protein Foxo1 in mouse liver results in 40% reduction of glucose levels at birth and 30% reduction in adult mice after a 48 hr fast. Gene expression and glucose clamp studies demonstrate that Foxo1 ablation impairs fasting- and cAMP-induced glycogenolysis and gluconeogenesis. Pgc1α is unable to induce gluconeogenesis in Foxo1-deficient hepatocytes, while the cAMP response is significantly blunted. Conversely, Foxo1 deletion in liver curtails excessive glucose production caused by generalized ablation of insulin receptors and prevents neonatal diabetes and hepatosteatosis in insulin receptor knockout mice. The data provide a unifying mechanism for regulation of hepatic glucose production by cAMP and insulin. The hallmark of type 2 diabetes is excessive hepatic glucose production. Several transcription factors and coactivators regulate this process in cultured cells. But gene ablation experiments have yielded few clues as to the physiologic mediators of this process in vivo. We show that inactivation of the gene encoding forkhead protein Foxo1 in mouse liver results in 40% reduction of glucose levels at birth and 30% reduction in adult mice after a 48 hr fast. Gene expression and glucose clamp studies demonstrate that Foxo1 ablation impairs fasting- and cAMP-induced glycogenolysis and gluconeogenesis. Pgc1α is unable to induce gluconeogenesis in Foxo1-deficient hepatocytes, while the cAMP response is significantly blunted. Conversely, Foxo1 deletion in liver curtails excessive glucose production caused by generalized ablation of insulin receptors and prevents neonatal diabetes and hepatosteatosis in insulin receptor knockout mice. The data provide a unifying mechanism for regulation of hepatic glucose production by cAMP and insulin. The mechanism by which hormones regulate hepatic glucose metabolism is a key question in biology with critical ramifications for pathogenesis and treatment of metabolic diseases (Matsumoto and Accili, 2006Matsumoto M. Accili D. The tangled path to glucose production.Nat. Med. 2006; 12: 33-34Crossref PubMed Scopus (16) Google Scholar). Hepatic glucose production (HGP) can be viewed as the product of the opposing actions of glucagon, acting through cAMP-dependent pathways, and insulin, acting through the PI 3-kinase pathway. Acute hormonal effects are independent of protein synthesis (Exton and Park, 1968Exton J.H. Park C.R. Control of gluconeogenesis in liver. II. Effects of glucagon, catecholamines, and adenosine 3′,5′-monophosphate on gluconeogenesis in the perfused rat liver.J. Biol. Chem. 1968; 243: 4189-4196Abstract Full Text PDF PubMed Google Scholar, Grempler et al. 2005Grempler R. Gunther S. Steffensen K.R. Nilsson M. Barthel A. Schmoll D. Walther R. Evidence for an indirect transcriptional regulation of glucose-6-phosphatase gene expression by liver X receptors.Biochem. Biophys. Res. Commun. 2005; 338: 981-986Crossref PubMed Scopus (16) Google Scholar, Sasaki et al. 1984Sasaki K. Cripe T.P. Koch S.R. Andreone T.L. Petersen D.D. Beale E.G. Granner D.K. Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin.J. Biol. Chem. 1984; 259: 15242-15251Abstract Full Text PDF PubMed Google Scholar) and transcriptional in nature (O'Brien and Granner, 1996O'Brien R.M. Granner D.K. Regulation of gene expression by insulin.Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (424) Google Scholar). Ambiguity persists on the identity and interactions of hormone-regulated factors controlling transcription of rate-limiting glucogenic enzymes, such as phosphoenolpyruvate carboxykinase (Pck1) and glucose-6 phosphatase (G6pc) (O'Brien and Granner, 1996O'Brien R.M. Granner D.K. Regulation of gene expression by insulin.Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (424) Google Scholar). The Creb-Torc2 pathway is acutely activated by cAMP to promote HGP in a Pgc1α-dependent manner , but does not respond to insulin (Koo et al., 2005Koo S.H. Flechner L. Qi L. Zhang X. Screaton R.A. Jeffries S. Hedrick S. Xu W. Boussouar F. Brindle P. et al.The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.Nature. 2005; 437: 1109-1111Crossref PubMed Scopus (730) Google Scholar). The coactivator Cbp is recruited to Creb when the latter is phosphorylated (Chrivia et al., 1993Chrivia J.C. Kwok R.P. Lamb N. Hagiwara M. Montminy M.R. Goodman R.H. Phosphorylated CREB binds specifically to the nuclear protein CBP.Nature. 1993; 365: 855-859Crossref PubMed Scopus (1735) Google Scholar). It has been shown that insulin phosphorylates Cbp to inhibit gluconeogenesis by disrupting the Creb/Cbp complex (Zhou et al., 2004Zhou X.Y. Shibusawa N. Naik K. Porras D. Temple K. Ou H. Kaihara K. Roe M.W. Brady M.J. Wondisford F.E. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein.Nat. Med. 2004; 10: 633-637Crossref PubMed Scopus (113) Google Scholar). However, the recent demonstration that Creb is promiscuously phosphorylated by both cAMP and insulin (Koo et al., 2005Koo S.H. Flechner L. Qi L. Zhang X. Screaton R.A. Jeffries S. Hedrick S. Xu W. Boussouar F. Brindle P. et al.The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.Nature. 2005; 437: 1109-1111Crossref PubMed Scopus (730) Google Scholar) makes this explanation problematic. Among transcriptional coactivators, Pgc1α is induced by fasting and is required for the Creb-Torc2 induction of gluconeogenesis (Koo et al., 2004Koo S.H. Satoh H. Herzig S. Lee C.H. Hedrick S. Kulkarni R. Evans R.M. Olefsky J. Montminy M. PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.Nat. Med. 2004; 10: 530-534Crossref PubMed Scopus (456) Google Scholar). But it is disputed whether Pgc1α is itself the target of insulin regulation (Herzig et al., 2001Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. et al.CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.Nature. 2001; 413: 179-183Crossref PubMed Scopus (1051) Google Scholar) or is regulated via Foxo1 (Puigserver et al., 2003Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. et al.Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1090) Google Scholar, Yoon et al., 2001Yoon J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. et al.Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.Nature. 2001; 413: 131-138Crossref PubMed Scopus (1436) Google Scholar). And the phenotype of Pgc1α-deficient mice is notable for the absence of significant abnormalities of glucose production (Lin et al., 2004Lin J. Wu P.H. Tarr P.T. Lindenberg K.S. St-Pierre J. Zhang C.Y. Mootha V.K. Jager S. Vianna C.R. Reznick R.M. et al.Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice.Cell. 2004; 119: 121-135Abstract Full Text Full Text PDF PubMed Scopus (940) Google Scholar). The forkhead transcription factor Foxo1 confers insulin responsiveness onto G6pc expression (Nakae et al., 2001Nakae J. Kitamura T. Silver D.L. Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.J. Clin. Invest. 2001; 108: 1359-1367Crossref PubMed Scopus (466) Google Scholar) by interacting with Pgc1α (Puigserver et al., 2003Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. et al.Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1090) Google Scholar). Nonetheless, its involvement in HGP has been evinced exclusively from gain-of-function or partial loss-of-function studies (Nakae et al., 2001Nakae J. Kitamura T. Silver D.L. Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.J. Clin. Invest. 2001; 108: 1359-1367Crossref PubMed Scopus (466) Google Scholar, Nakae et al., 2002Nakae J. Biggs W.H. Kitamura T. Cavenee W.K. Wright C.V. Arden K.C. Accili D. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.Nat. Genet. 2002; 32: 245-253Crossref PubMed Scopus (510) Google Scholar, Puigserver et al., 2003Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. et al.Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1090) Google Scholar, Samuel et al., 2006Samuel V.T. Choi C.S. Phillips T.G. Romanelli A.J. Geisler J.G. Bhanot S. McKay R. Monia B. Shutter J.R. Lindberg R.A. et al.Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action.Diabetes. 2006; 55: 2042-2050Crossref PubMed Scopus (143) Google Scholar), leading to controversy as to whether it is required for either the Pgc1α (Schilling et al., 2006Schilling M.M. Oeser J.K. Boustead J.N. Flemming B.P. O'Brien R.M. Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection.Nature. 2006; 443: E10-E11Crossref PubMed Scopus (51) Google Scholar) or the insulin response (Herzig et al., 2001Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. et al.CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.Nature. 2001; 413: 179-183Crossref PubMed Scopus (1051) Google Scholar, Yeagley et al., 2001Yeagley D. Guo S. Unterman T. Quinn P.G. Gene- and activation-specific mechanisms for insulin inhibition of basal and glucocorticoid-induced insulin-like growth factor binding protein-1 and phosphoenolpyruvate carboxykinase transcription. Roles of forkhead and insulin response sequences.J. Biol. Chem. 2001; 276: 33705-33710Crossref PubMed Scopus (93) Google Scholar). Although a dominant negative Foxo1, lacking the transactivation domain, reduces gluconeogenesis (Nakae et al., 2001Nakae J. Kitamura T. Silver D.L. Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.J. Clin. Invest. 2001; 108: 1359-1367Crossref PubMed Scopus (466) Google Scholar) and reverses hyperglycemia in ob/ob mice (Altomonte et al., 2003Altomonte J. Richter A. Harbaran S. Suriawinata J. Nakae J. Thung S.N. Meseck M. Accili D. Dong H. Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice.Am. J. Physiol. Endocrinol. Metab. 2003; 285: E718-E728PubMed Google Scholar), this approach is tainted by potential off-target effects of the mutant Foxo1. To examine this question, we ablated Foxo1 expression in mouse hepatocytes using cre-loxP mutagenesis. To ablate Foxo1 in hepatocytes, we intercrossed mice homozygous for a floxed Foxo1 allele (Paik et al., 2007Paik J.H. Kollipara R. Chu G. Ji H. Xiao Y. Ding Z. Miao L. Tothova Z. Horner J.W. Carrasco D.R. et al.FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis.Cell. 2007; 128: 309-323Abstract Full Text Full Text PDF PubMed Scopus (802) Google Scholar) with α1 antitrypsin-cre mice (henceforth, l-Foxo1 mice). Hepatic Foxo1 mRNA (Figures 1A and 1B) and protein (Figure 1C) levels were decreased by ∼90% in l-Foxo1 mice, compared to controls. In contrast, expression of the isoform Foxo3a was unchanged (Figure 1B) as was expression of Foxa2, a related transcription factor that regulates liver metabolism (Wolfrum et al., 2004Wolfrum C. Asilmaz E. Luca E. Friedman J.M. Stoffel M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes.Nature. 2004; 432: 1027-1032Crossref PubMed Scopus (295) Google Scholar, Zhang et al., 2005Zhang L. Rubins N.E. Ahima R.S. Greenbaum L.E. Kaestner K.H. Foxa2 integrates the transcriptional response of the hepatocyte to fasting.Cell Metab. 2005; 2: 141-148Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar) (Figure 1C). At birth, l-Foxo1 mice showed a 40% decrease of blood glucose level (Figure 1D), while hepatic glycogen increased (Figure 1E and data not shown). In adult mice, fasting induced glycogenolytic (G6pc) and gluconeogenetic genes (Pck1 and Ppargc1α) 2- to 4-fold. In l-Foxo1 mice, G6pc expression failed to increase with fasting, while the rise of Pck1 and Ppargc1α was curtailed by ∼50%, as was expression of two Foxo1 target genes, insulin-like growth factor binding protein-1 (Igfbp1) (Guo et al., 1999Guo S. Rena G. Cichy S. He X. Cohen P. Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence.J. Biol. Chem. 1999; 274: 17184-17192Crossref PubMed Scopus (458) Google Scholar), and insulin receptor substrate 2 (Irs2) (Zhang et al., 2001Zhang J. Ou J. Bashmakov Y. Horton J.D. Brown M.S. Goldstein J.L. Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes.Proc. Natl. Acad. Sci. USA. 2001; 98: 3756-3761Crossref PubMed Scopus (88) Google Scholar) (Figure 2A). In contrast, Foxo1-independent metabolic pathways, such as those mediated by Srebf1c (Horton et al., 2003Horton J.D. Shah N.A. Warrington J.A. Anderson N.N. Park S.W. Brown M.S. Goldstein J.L. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.Proc. Natl. Acad. Sci. USA. 2003; 100: 12027-12032Crossref PubMed Scopus (996) Google Scholar) and glucokinase (Gck) (Dentin et al., 2004Dentin R. Pegorier J.P. Benhamed F. Foufelle F. Ferre P. Fauveau V. Magnuson M.A. Girard J. Postic C. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression.J. Biol. Chem. 2004; 279: 20314-20326Crossref PubMed Scopus (328) Google Scholar), were unaffected (Figure 2A). These data indicate that deletion of Foxo1 affected only the expression of Foxo1 target genes and did not result in widespread hepatotoxicity (Table 1). Consistent with the changes in glucogenetic gene expression, l-Foxo1 mice showed 30% lower blood glucose levels compared with control mice after prolonged (48 hr) fasting (Figure 2B). Notably, 10% of the l-Foxo1 mice developed neuroglycopenia, with seizures that were relieved by glucose administration.Table 1Metabolic Characteristics of 16-Week-Old l-Foxo1 MiceParameterControll-Foxo1Body weight (g)27.5 ± 0.728.0 ± 1.3Fat mass (g)2.41 ± 0.282.81 ± 0.44Fat mass/BW (%)8.68 ± 2.7910.10 ± 1.39Lean mass (g)22.6 ± 0.522.6 ± 1.2Lean mass/BW (%)82.48 ± 0.9080.78 ± 1.03Liver (g)1.25 ± 0.071.24 ± 0.05Liver/BW (%)4.28 ± 0.144.47 ± 0.11Fed Glucose (mg/dl)177 ± 15161 ± 17Glucose (mg/dl)127 ± 9131 ± 16Fed Insulin (ng/ml)1.04 ± 0.100.91 ± 0.07Insulin (ng/ml)0.45 ± 0.110.40 ± 0.07Triglyceride (mg/dl)54 ± 560 ± 7Cholesterol (mg/dl)102 ± 5115 ± 6NEFA (mEq/l)0.59 ± 0.030.65 ± 0.07β-Hydroxybutyrate (mM)0.69 ± 0.080.89 ± 0.17Fed Liver triglyceride (mg/g)15.9 ± 1.818.6 ± 1.3Liver triglyceride (mg/g)66.7 ± 4.772.5 ± 4.8Liver cholesterol (mg/g)5.8 ± 0.25.5 ± 0.2Fed Liver glycogen (mg/g)20.86 ± 3.5616.83 ± 3.50AST (IU/l)27 ± 128 ± 1ALT (IU/l)3 ± 13 ± 0.1γ-GTP (IU/l)9 ± 310 ± 1ALP (IU/l)23 ± 123 ± 1Albumin (g/dl)20.9 ± 3.616.8 ± 3.5All data, unless otherwise indicated, were obtained in overnight-fasted animals. No difference achieved statistical significance. Open table in a new tab All data, unless otherwise indicated, were obtained in overnight-fasted animals. No difference achieved statistical significance. To evaluate the effects of altered gene expression on HGP, we conducted pyruvate challenge tests in 16-week-old mice. Glucose levels were significantly lower in l-Foxo1 mice in response to pyruvate administration (Figure 2C). Moreover, adult l-Foxo1 mice (Table 1) showed reduced glucose excursions during glucose tolerance tests compared with control mice (Figure 2D), while insulin tolerance tests were identical in both groups (Figure 2E). In hyperinsulinemic euglycemic clamps, l-Foxo1 mice required a 30% increase of the glucose infusion rate to maintain euglycemia, consistent with a state of heightened insulin sensitivity (Figure 2F). Despite this, HGP in l-Foxo1 was > 50% lower than control mice (Figure 2G), while peripheral glucose uptake was unaffected (Figure 2H). The combination of increased glucose infusion and reduced HGP, in the absence of changes in peripheral glucose uptake, indicates that glucose is primarily incorporated into hepatic glycogen. To analyze changes in hepatic glucose fluxes, we measured glucose cycling, glycogenolysis, and gluconeogenesis. Glucose cycling, i.e., the amount of glucose-6-phosphate that is dephosphorylated and released without being further metabolized (Vranic, 1992Vranic M. Banting Lecture: glucose turnover. A key to understanding the pathogenesis of diabetes (indirect effects of insulin).Diabetes. 1992; 41: 1188-1206Crossref PubMed Scopus (30) Google Scholar), decreased by >60% in l-Foxo1 mice, consistent with reduced flux through G6pc (Figure 2I). Glycogenolysis and gluconeogenesis were both decreased by ∼50% (Figure 2J and 2K), consistent with the gene expression data (Figure 2A). Moreover, fasting hepatic glycogen content in l-Foxo1 mice increased 6-fold (Figure 2L). These results indicate that Foxo1 ablation in liver suppresses HGP by decreasing both glycogenolysis and gluconeogenesis. Pgc1α mediates HGP during fast (Herzig et al., 2001Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. et al.CREB regulates hepatic gluconeogenesis through the coactivator PGC-1.Nature. 2001; 413: 179-183Crossref PubMed Scopus (1051) Google Scholar, Yoon et al., 2001Yoon J.C. Puigserver P. Chen G. Donovan J. Wu Z. Rhee J. Adelmant G. Stafford J. Kahn C.R. Granner D.K. et al.Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1.Nature. 2001; 413: 131-138Crossref PubMed Scopus (1436) Google Scholar) in a Torc2-dependent manner (Koo et al., 2005Koo S.H. Flechner L. Qi L. Zhang X. Screaton R.A. Jeffries S. Hedrick S. Xu W. Boussouar F. Brindle P. et al.The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.Nature. 2005; 437: 1109-1111Crossref PubMed Scopus (730) Google Scholar). It has been disputed (Schilling et al., 2006Schilling M.M. Oeser J.K. Boustead J.N. Flemming B.P. O'Brien R.M. Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection.Nature. 2006; 443: E10-E11Crossref PubMed Scopus (51) Google Scholar) whether Foxo1 is required for the Pgc1α response (Puigserver et al., 2003Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. et al.Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1090) Google Scholar). To address this question, we analyzed Pgc1α's ability to regulate glucogenic genes in hepatocytes lacking Foxo1. In hepatocytes derived from control mice, transduction of Pgc1α increased G6pc and Pck1 expression ∼2,500- and 80-fold, respectively (Figure 3, empty bars). Insulin partly inhibited Pgc1α-induced gene expression. In Foxo1-deficient hepatocytes, Pgc1α induction of either gene decreased by >95% (Figure 3, full bars). In contrast, Pgc1α induction of Cycs and Atp5b genes, which are not regulated by Foxo1, was preserved. These data indicate that Foxo1 is required for Pgc1α induction of hepatic glucogenetic genes. We next assessed the effect of Foxo1 inactivation in primary hepatocytes, using a short-hairpin (sh) RNA adenovirus to reduce Foxo1 expression by ∼90% (Figure 4A). We examined gene expression induced by cAMP (G6pc), dexamethasone (Igfbp1), or both (Pck1 and Ppargc1a). In all instances, Foxo1 ablation reduced the hormonal response by ∼50% to ∼70% (Figure 4B), indicating that Foxo1 plays a role in both cAMP and glucocorticoid induction of hepatic gene expression. Consistent with these results, Foxo1 shRNA curtailed basal and prevented cAMP-induced glucose release in the medium (Figure 4C). Moreover, expression of Foxo1 target genes in the insulin signaling pathway was also decreased by ∼50%, with a commensurate decrease of insulin-induced phosphorylation (Figure 4D and 4E) (Gershman et al., 2007Gershman B. Puig O. Hang L. Peitzsch R.M. Tatar M. Garofalo R.S. High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO.Physiol. Genomics. 2007; 29: 24-34Crossref PubMed Scopus (133) Google Scholar, Ide et al., 2004Ide T. Shimano H. Yahagi N. Matsuzaka T. Nakakuki M. Yamamoto T. Nakagawa Y. Takahashi A. Suzuki H. Sone H. et al.SREBPs suppress IRS-2-mediated insulin signalling in the liver.Nat. Cell Biol. 2004; 6: 351-357Crossref PubMed Scopus (266) Google Scholar, Matsumoto et al., 2006Matsumoto 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: 2464-2472PubMed Google Scholar, Puig and Tjian, 2005Puig O. Tjian R. Transcriptional feedback control of insulin receptor by dFOXO/FOXO1.Genes Dev. 2005; 19: 2435-2446Crossref PubMed Scopus (257) Google Scholar, Zhang et al., 2001Zhang J. Ou J. Bashmakov Y. Horton J.D. Brown M.S. Goldstein J.L. Insulin inhibits transcription of IRS-2 gene in rat liver through an insulin response element (IRE) that resembles IREs of other insulin-repressed genes.Proc. Natl. Acad. Sci. USA. 2001; 98: 3756-3761Crossref PubMed Scopus (88) Google Scholar). These changes in gene expression attenuated insulin signaling in hepatocytes expressing Foxo1 shRNA (Figure 4E). We also studied the cAMP response in primary hepatocytes from l-Foxo1 mice. We observed a 50% decrease in G6pc induction and a 30% decrease in Ppargc1a induction, whereas Pck1 expression was unaffected (Figure 4F). Glucose release in the medium decreased by ∼25% (Figure 4G). The difference between the knockdown and knockout hepatocytes indicates that adaptive mechanisms (e.g., Foxo3) can compensate for chronic, but not for acute, Foxo1 ablation. In diabetes, fasting hyperglycemia reflects an altered balance between the insulin and glucagon effects on HGP (Cherrington, 1999Cherrington A.D. Banting Lecture 1997. Control of glucose uptake and release by the liver in vivo.Diabetes. 1999; 48: 1198-1214Crossref PubMed Scopus (381) Google Scholar). Foxo1 gain-of-function, dominant negative inhibition, and generalized haploinsufficiency (Nakae et al., 2001Nakae J. Kitamura T. Silver D.L. Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression.J. Clin. Invest. 2001; 108: 1359-1367Crossref PubMed Scopus (466) Google Scholar, Nakae et al., 2002Nakae J. Biggs W.H. Kitamura T. Cavenee W.K. Wright C.V. Arden K.C. Accili D. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.Nat. Genet. 2002; 32: 245-253Crossref PubMed Scopus (510) Google Scholar) have shown impairment and potentiation, respectively, of insulin action on HGP. But these results are neither unique to Foxo1 (Hall et al., 2000Hall R.K. Yamasaki T. Kucera T. O'Brien R.M. Granner D.K. Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor binding protein-1 gene expression by insulin.J. Biol. Chem. 2000; 275: 30169-30175Crossref PubMed Scopus (233) Google Scholar, Inoue et al., 2004Inoue H. Ogawa W. Ozaki M. Haga S. Matsumoto M. Furukawa K. Hashimoto N. Kido Y. Mori T. Sakaue H. et al.Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo.Nat. Med. 2004; 10: 168-174Crossref PubMed Scopus (288) Google Scholar, Zhang et al., 2005Zhang L. Rubins N.E. Ahima R.S. Greenbaum L.E. Kaestner K.H. Foxa2 integrates the transcriptional response of the hepatocyte to fasting.Cell Metab. 2005; 2: 141-148Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar) nor conclusive that Foxo1 is the physiologic mediator of insulin signaling to HGP (Schilling et al., 2006Schilling M.M. Oeser J.K. Boustead J.N. Flemming B.P. O'Brien R.M. Gluconeogenesis: re-evaluating the FOXO1-PGC-1alpha connection.Nature. 2006; 443: E10-E11Crossref PubMed Scopus (51) Google Scholar, Yeagley et al., 2001Yeagley D. Guo S. Unterman T. Quinn P.G. Gene- and activation-specific mechanisms for insulin inhibition of basal and glucocorticoid-induced insulin-like growth factor binding protein-1 and phosphoenolpyruvate carboxykinase transcription. Roles of forkhead and insulin response sequences.J. Biol. Chem. 2001; 276: 33705-33710Crossref PubMed Scopus (93) Google Scholar). We tested Foxo1's role in genetic epistasis experiments. In C.elegans, Daf16 (Foxo) ablation reverses the dauer phenotype of Daf2 (Insr) mutants (Lin et al., 1997Lin K. Dorman J.B. Rodan A. Kenyon C. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans.Science. 1997; 278: 1319-1322Crossref PubMed Scopus (1153) Google Scholar, Ogg et al., 1997Ogg S. Paradis S. Gottlieb S. Patterson G.I. Lee L. Tissenbaum H.A. Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans.Nature. 1997; 389: 994-999Crossref PubMed Scopus (1468) Google Scholar). We hypothesized that, if Foxo1 is indeed in the genetic pathway of insulin action, lack of Foxo1 should reverse the abnormalities induced by lack of Insr. To test the hypothesis, we intercrossed insulin receptor-deficient (Insr−/−) and l-Foxo1 mice to obtain double knockouts (Dko) lacking Insr in all tissues and Foxo1 in liver. Insr−/− mice develop lethal neonatal diabetic ketoacidosis and steatosis (Figures 5A–5C) (Accili et al., 1996Accili D. Drago J. Lee E.J. Johnson M.D. Cool M.H. Salvatore P. Asico L.D. Jose P.A. Taylor S.I. Westphal H. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene.Nat. Genet. 1996; 12: 106-109Crossref PubMed Scopus (458) Google Scholar), independent of their genetic background (Okamoto et al., 2004Okamoto H. Nakae J. Kitamura T. Park B.C. Dragatsis I. Accili D. Transgenic rescue of insulin receptor-deficient mice.J. Clin. Invest. 2004; 114: 214-223Crossref PubMed Scopus (113) Google Scholar). In Dko mice, metabolic abnormalities were reversed and survival extended (Figures 5A–5C). Expression of insulin- and cAMP-regulated genes (G6pc, Pck1, Ppargc1a, Igfbp1, and Irs2) decreased, while Gck expression increased (Figure 5D) (Zhang et al., 2006Zhang W. Patil S. Chauhan B. Guo S. Powell D.R. Le J. Klotsas A. Matika R. Xiao X. Franks R. et al.Foxo1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.J. Biol. Chem. 2006; 281: 10105-10117Crossref PubMed Scopus (362) Google Scholar). Approximately 5% of Dko mice survived to adulthood and, at 14 weeks of age, they developed severe diabetes with growth retardation, hepatomegaly, extreme insulin resistance, hyperketonemia, and dyslipidemia (Figure 5E). Histological analyses indicated lipoatrophy specifically in white adipose tissue (Figure 5F) and β cell hyperplasia (Figure 5G). Dko mice phenocopy Insr transgenic knockout mice with restored Insr expression in liver (Okamoto et al., 2004Okamoto H. Nakae J. Kitamura T. Park B.C. Dragatsis I. Accili D. Transgenic rescue of insulin receptor-deficient mice.J. Clin. Invest. 2004; 114: 214-223Crossref PubMed Scopus (113) Google Scholar), indicating that Foxo1 is the primary mediator of hepatic insulin signaling. The absence of steatosis in Dko mice raises the possibility that Foxo1 controls hepatic lipid synthesis (Matsumoto et al., 2006Matsumoto 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: 2464-2472PubMed Google Scholar), in addition to HPG. Our results provide the hitherto missing, critical test of the hypothesis that Foxo1 is required for hormonal regulation of HGP. We now show that hepatic Foxo1 ablation results in the following: (1) 40% reduction of glucose levels at birth, when glucogenetic genes are first induced (Girard et al., 1992Girard J. Ferre P. Pegorier J.P. Duee P.H. Adaptations of glucose and fatty acid metabolism during perinatal period and suckling-weaning transition.Physiol. Rev. 1992; 72: 507-562Crossref PubMed Scopus (387) Google Scholar); (2) 30% reduction of glucose levels in adult mice after prolonged (48 hr) fasting; (3) fasting-induced neuroglycopenia in 10% of l-Foxo1 mice; (4) blunted induction of glucogenetic genes with fasting; and (5) 50% decrease of glycogenolysis and gluconeogenesis during hyperinsulinemic euglycemic clamps. The data show a surprising role for Foxo1 as the shared element coordinating HGP control by cAMP and insulin. Although we have previously shown that Foxo1 plays a role in insulin inhibition of cAMP-induced glucose production (Nakae et al., 2001Nakae J. Kitamura T. Silver D.L. Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase" @default.
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• W2009010832 title "Impaired Regulation of Hepatic Glucose Production in Mice Lacking the Forkhead Transcription Factor Foxo1 in Liver" @default.
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