CREB and FoxO1: two transcription factors for the regulation of hepatic gluconeogenesis

  • Received : 2013.10.17
  • Published : 2013.12.31


Liver plays a major role in maintaining glucose homeostasis in mammals. Under fasting conditions, hepatic glucose production is critical as a source of fuel to maintain the basic functions in other tissues, including skeletal muscle, red blood cells, and the brain. Fasting hormones glucagon and cortisol play major roles during the process, in part by activating the transcription of key enzyme genes in the gluconeogenesis such as phosphoenol pyruvate carboxykinase (PEPCK) and glucose 6 phosphatase catalytic subunit (G6Pase). Conversely, gluconeogenic transcription is repressed by pancreatic insulin under feeding conditions, which effectively inhibits transcriptional activator complexes by either promoting post-translational modifications or activating transcriptional inhibitors in the liver, resulting in the reduction of hepatic glucose output. The transcriptional regulatory machineries have been highlighted as targets for type 2 diabetes drugs to control glycemia, so understanding of the complex regulatory mechanisms for transcription circuits for hepatic gluconeogenesis is critical in the potential development of therapeutic tools for the treatment of this disease. In this review, the current understanding regarding the roles of two key transcriptional activators, CREB and FoxO1, in the regulation of hepatic gluconeogenic program is discussed.


Glucose functions as a primary fuel for mammals. Thus, the maintenance of the glucose homeostasis is one of the primary mechanisms for the survival of the organisms. Intake of dietary carbohydrates and their absorption in the intestine provide one of the primary events to control the rate of glucose metabolism. In addition, utilization of glucose by skeletal muscles or adipocytes, as well as the glucose output by the liver, are also key components for controlling glucose homeostasis (1).

The liver is critical in maintaining glucose homeostasis, as an organ that controls the equilibrium of plasma and hepatic glucose levels by the regulated uptake and storage process and the output of glucose (1-3). Under feeding conditions, the intake of carbohydrates is generally supplied to the bloodstream as a form of glucose via the intestinal system, which can be used by peripheral tissues such as skeletal muscle, red blood cells, and the brain. Excessive glucose in the liver is initially stored as glycogen via glycogenesis, and eventually processed as a triglyceride by a combination of metabolic pathways including glycolysis, fatty acid biosynthesis, triglyceride synthesis, and maturation. The latter process is termed as lipogenesis. The resultant triglyceride is converted into very low density lipoprotein (VLDL), and is transported into the white adipose tissues (4). Pancreatic insulin plays a major role in the process by activating key regulatory enzymes in the process by acute post-translational modifications. Furthermore, expression of genes involved in the lipogenesis is increased by transcription factors such as SREBP-1c and ChREBP. The roles of these transcription factors are described elsewhere (5-7). Under fasting conditions, the increase in glucagon levels that are associated with the decrease in insulin levels in the plasma is critical in the glucose output from the liver by initially enhancing glycogen breakdown. Prolonged fasting induces de novo glucose synthesis from the liver, termed gluconeogenesis, by acute activation of key regulatory enzymes that include glucose 6 phosphatase (G6Pase), fructose 1,6-bisphosphatase (Fbpase), pyruvate carboxylase (PC), and phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, chronic activation of gluconeogenesis is ultimately achieved by the transcriptional activation of the aforementioned gluconeogenic genes (2,3,8,9).

As major catabolic hormones, glucagon and stress hormone cortisol instigate the intracellular signaling pathways to activate key transcription factors such as cAMP response element binding protein (CREB) and forkhead box class Os (FoxOs) (10-13). Transcriptional co-activators are necessary to modulate the full activity of these transcription factors. The transcriptional co-activators that have been linked to these factors include CREB binding protein (CBP)/p300, CREB regulated transcription co-activator 2 (CRTC2), peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), and protein arginine methyltransferases (PRMTs) (14-19). On the other hand, the anabolic hormone insulin inhibits the gluconeogenic program either via inactivation of transcriptional activators/co-activators or activation of transcriptional repressors of gluconeogenic genes. Examples of the transcriptional repressors include orphan nuclear receptor SHP and Transcription factor 7-like2 (TCF7L2) (20-22).

In this review, we would like to delineate the molecular mechanisms by which CREB and FoxO1 control the hepatic gluconeogenic program. We will also provide the involvement of transcriptional co-activators and repressors to modulate the activity of transcriptional circuits for hepatic gluconeogenesis.



General facts

CREB is one the first transcription factors purified by DNA affinity column using the cyclic AMP binding element (CRE) of the somatostatin gene (23). G-protein coupled receptor (GPCR)-mediated activation of adenylyl cyclase increased levels of cyclic AMP in the cell, which activates protein kinase A (PKA) and the subsequent phosphorylation of Ser 133 of CREB. These phosphorylation events lead to the recruitment of histone acetyltransferasese CBP/p300 onto the promoter, and resultant acetylation of histones H3 and H4 (24-26). In addition, CREB-dependent transcription is further enhanced by association with its CRTC transcriptional co-activators (27,28). Attenuation of CREB activity can be achieved by dephosphorylation of this residue by Ser/Thr phosphatases such as protein phosphatase 1 (PP1) and PP2A (29,30).

Regulation of hepatic gluconeogenesis

Under fasting conditions, increased secretion of pancreatic glucagon leads to the activation of cAMP-CREB-dependent gluconeogenesis in the liver. The presence of CRE on the promoters of key gluconeogenic genes including PEPCK, G6Pase, Fbpase, and PC were identified, and it was subsequently confirmed that CREB could directly activate the transcription of these genes (31). The significance of CREB in the regulation of hepatic gluconeogenesis was shown by a study utilizing alb-ACREB TG mice that express ACREB, a dominant negative inhibitor of CREB, in the liver (10). Alb-ACREB TG mice result in the reduction in blood glucose levels with reduced mRNA levels for hepatic gluconeogenic genes, showing that CREB is a physiological transcriptional regulator of gluconeogenesis in vivo. Furthermore, acute inhibition of CREB activity by the delivery of adenoviral ACREB, siRNA for CREB, or inhibitory chemicals also reduces blood glucose levels in vivo, suggesting that CREB could be a potential target for the development of anti-diabetes drugs (10,32).

Transcriptional co-activators for CREB

CBP/p300: CBP and its orthologue p300 are members of histone acetyltransferases (HATs) acetylate lysine residues of both histone and non-histone proteins (33,34). Homozygotic null mice for either CBP or p300 are embryonically lethal, showing that they are critical in the process of embryonic development (35,36).

As a transcriptional co-activator for CREB, the role of CBP/p300 has been implicated in glucose metabolism. The role for CBP in gluconeogenesis is still unresolved. While mice heterozygous for a CBP mutant allele showed insulin sensitive phenotypes in an earlier report, recent studies utilizing CBP mutant mice revealed that the disruption of CREB-CBP interaction did not result in reduced hepatic gluconeogenesis (16,37). Furthermore, mice containing CBP with mutations in CH1 domain are resistant to insulin-mediated regulation of hepatic gluconeogenesis, and mutant mice producing CH1 null products (ΔCH1) display normal fasting gluconeogenesis (14,38,39). These data suggest that CBP alone is not sufficient to regulate CREB activity in mediating hepatic gluconeogenesis. Further studies are necessary to delineate the potential involvement of p300 and other HATs in the transcriptional control in this setting.

CRTC2: The CRTC family of transcriptional co-activators (also known as TORC, transducers of regulated CREB activity) consists of CRTC1, CRTC2, and CRTC3, which possess an N-terminal CREB binding domain, a central regulatory domain that is Ser/Pro-rich, and a C-terminal transactivation domain (40). The activity of the CRTC family mainly regulates phosphorylation-dependent changes in cellular localization. Under basal conditions, CRTCs are highly phosphorylated and reside in the cytosol via interaction with 14-3-3 proteins. Most notably, phosphorylation of Ser 171 (for CRTC2) is mediated by AMP-activated protein kinase (AMPK) and its related kinases (AMPKRK) such as salt-inducible kinase 1(SIK1) and SIK2. Exposure to cAMP agonist or the treatment of calcium ionophore directs a rapid dephosphorylation of CRTCs by inactivation of kinases and activation of Ser/Thr phosphatases (e.g. as PP2B or SMEK/PP4C) (41-43).

CRTC2 is the most prominent isoform in the mammalian liver. Fasting-dependent dephosphorylation of CRTC2 results in its nuclear translocation and interaction with CREB to activate hepatic gluconeogenesis (16). Recent studies also revealed the physiological significance of CRTC2 in the regulation of hepatic gluconeogenesis. Acute knockdown of CRTC2 in mice by RNA interference reduces fasting plasma glucose with reduction in gluconeogenic gene expression (16,44). Similarly, CRTC2 knockout mice exhibit low blood glucose levels and increased glucose tolerance, confirming that CRTC2 is critical in the control of hepatic gluconeogenesis and energy homeostasis (45). CRTC2 was also shown to co-activate other basic leucine zipper transcription factors such as CREBH and ATF6, each of which could influence glucose homeostasis in mammals (12,46). Further study is required for the potential competition between transcription factors to recruit the CRTC2 as a transcriptional co-activator.

Downstream targets for CREB in the energy metabolism

CREB is not only important in the direct transcriptional activation of gluconeogenic genes, but is also critical in modulating the fasting-mediated transcriptional activation of PGC-1α and estrogen-related receptor gamma (ERRγ), which serve as crucial transcriptional regulators for the activation of gluconeogenic genes during the prolonged fasting or starvation (10,11,19). We have also identified that mammalian phosphatidic acid phosphatase Lipin1 is a transcriptional target of CREB, and is responsible for the progression of hepatic insulin resistance in the diet-induced or the genetic mouse models of obesity (47). Thus, further study is necessary to delineate the diverse roles of CREB in the transcriptional control of energy homeostasis.



General facts

FoxOs belong to a subclass within the forkhead family of transcription factors that possess a forkhead box-type DNA binding domain, which recognize a specific regulatory element termed insulin response element (IRE) on the promoter. Four major isoforms, FoxO1, FoxO3, FoxO4, and FoxO6 are identified in mammals, and they function as critical transcription factors for various cellular signaling pathways in the energy metabolism, stress resistance, and longevity (48,49).

As in the case of CRTCs, subcellular localization of FoxOs is determined by the phosphorylation status of Ser/Thr residues. Insulin/PI3K signaling pathway activates Akt/serum and glucocorticoid-induced kinase (SGK)-dependent phosphorylation of key Ser/Thr residues of FoxOs (Thr24, Ser253, and Ser316 for murine FoxO1), which promotes association with 14-3-3, the cytoplasmic localization, and subsequent degradation by a ubiquitin/proteasome-mediated pathway (50-52). Additionally, acetylation of FoxOs (at Lys242, 245, and 262 for murine FoxO1) could also modulate their transcriptional activity, though the exact outcome of such modification is still in debate (53-55).

Regulation of hepatic gluconeogenesis

Among FoxO family members, FoxO1 has been tightly linked with hepatic gluconeogenesis (56). FoxO1 binding sites (IRE) were mapped on the promoters of G6Pase and PEPCK, and were shown to be critical in mediating the insulin/Akt-dependent inhibition of these genes (57). Further study revealed that in conjunction with PGC-1α, FoxO1 confers insulin-dependent regulation of hepatic gluconeogenesis in mouse models (18). Chronic deletion of FoxO1 in the liver also results in reduced hepatic glucose production in mice, showing that FoxO1 is indeed a major transcription factor for modulating hepatic gluconeogenesis (56,58). Recently, a role of FoxO6, another member of the FoxO family, was demonstrated in hepatic gluconeogenesis, suggesting that some redundancy might be present among FoxO transcription factors in the control of hepatic glucose metabolism in vivo (59).

Transcriptional co-activators for FoxO1

PGC-1α: First identified as a co-activator of PPARγ, PGC-1α plays a crucial role in the control of adaptive thermogenesis in response to cold shock in brown adipocytes (60). PGC-1α is also shown to interact with other transcriptional co-activators such as CBP/p300 and the mediator complex to fully activate transcriptional initiation (61,62). Initially, PGC-1α can only function as a co-activator for nuclear receptors such as PPARα, PPARδ, liver X receptor (LXR)α/β, GR, retinoid-related orphan nuclear receptor (ROR) subfamily, and farnesoid X receptor (FXR) using its LXXLL motifs. PGC-1α was also shown to co-activate various types of transcription factors, such as SREBP, Sox9, and FoxO1 (63,64).

In the liver, the expression of PGC-1α is markedly induced upon fasting via a CREB-dependent transcriptional mechanism, and is critical in maintaining prolonged gluconeogenesis under starvation (10,19). Indeed, PGC-1α promotes the expression of gluconeogenic genes by enhancing the transactivating potential of FoxO1 (10,18,19). Conversely, the depletion of PGC-1α in the liver of mice results in the reduction of fasting glucose levels with the reduced expression of gluconeogenic genes (65,66). These data underscore the physiological role of PGC-1α as a transcriptional co-activator for FoxO1 in the regulation of hepatic gluconeogenesis.

PRMTs: Protein arginine methyltransferases (PRMTs) catalyze the transfer of (a) methyl group to the Arg residues of histones and non-histone proteins in eukaryotes. PRMT1 is among the eleven mammalian PRMTs that have been identified in mammals to date, and belongs to the type I enzymes that include PRMT1, 3, 4, 6, and 8. It catalyzes the formation of asymmetrically dimethylated Arg on its substrates. FoxO1 was recently identified as a substrate for PRMT1, and Arg methylation of FoxO1 at Arg248 and 250 by PRMT1 enhances nuclear localization of FoxOs, thereby promoting downstream signaling such as oxidative stress response (15,67-69).

The role of PRMT1 as a co-activator for FoxO1 in the hepatic gluconeogenesis was recently established (15,67). In mouse liver, PRMT1-dependent Arg-dimethylation increases nuclear localization and chromatin occupancy of FoxO1 on the gluconeogenic promoter. Furthermore, either acute knockdown or chronic haploinsufficiency of PRMT1 in mice reduces FoxO1-mediated gluconeogenesis, showing that PRMT1 is critical in enhancing FoxO1 activity in the physiological context. Further study is required to explore the potential involvement of other PRMT families in the regulation of gluconeogenesis or FoxO1 activity.




SHP, also known as NR0B2, is a member of atypical nuclear receptors (NRs) that lack a DNA-binding motif, and mostly functions as a transcriptional repressor of NRs via its LXXLL motifs (70,71). In addition, SHP can inhibit the activity of other classes of transcription factors, suggesting that atypical NRs might function as a more general transcriptional repressor for various cellular signaling pathways.

SHP is ubiquitously expressed in most tissues but shows a higher expression in the mammalian liver, suggesting a role in the regulation of hepatic energy metabolism (72,73). Indeed, metformin-dependent activation of AMPK leads to the transcriptional induction of SHP in the liver, which in turn reduces hepatic glucose output in mice, showing a novel mechanism for this glucose-lowering reagent (74). Subsequently, it was shown that SHP directly inhibits cAMP-dependent hepatic gluconeogenesis by binding to CREB to block the association with CRTC2 (20). These results illustrate an alternative mechanism by which metformin regulates hepatic glucose production via SHP-dependent inhibition of gluconeogenic gene transcription. It is worth noting that DAX-1, another member of atypical NRs, reduces hepatic glucose production by inhibiting the recruitment of another transcription co-activator for gluconeogenesis, PGC-1α, onto the promoters of PEPCK and G6Pase. Further study is necessary to delineate the physiological and pathological relevance of these atypical NRs in the regulation of glucose homeostasis.

Fig. 1.Models for transcriptional regulation of hepatic gluconeogenesis under fasting and feeding conditions. (A) Transcriptional activation of hepatic gluconeogenesis under fasting conditions. Under fasting conditions, increased secretion of pancreatic glucagon triggers activation of PKA, which phosphorylates CREB at the serine 133 residue, leading to the increased association of this factor with co-activator CBP/p300 onto the chromatin. In addition, PKA promotes dephosphorylation of CRTC2 at the serine 171 residue by inactivating SIK kinases and activating serine/threonine phosphatases SMEK/PP4C and PP2B, leading to the nuclear localization and increased association of CRTC2 with chromatin-bound CREB. These events lead to the increased expression of gluconeogenic genes such as PEPCK and G6Pase, leading to the increases in hepatic gluconeogenesis during the early phase of fasting. At the same time, CREB/CRTC2 can enhance the expression of PGC-1α and ERRγ, which are the key transcriptional regulators of hepatic gluconeogenesis during the later phase of fasting. PRMP1 is also involved in the regulation of gluconeogenesis by modifying the arginine residues (Arg 248 and 250) of FoxO1 during this process. (B) Transcriptional repression of hepatic gluconeogenesis under feeding conditions. By contrast, feeding leads to the reduced plasma concentration of glucagon and enhanced secretion of pancreatic insulin, which leads to the activation of insulin signaling pathways in the liver. Activation of Akt leads to the activation of SIK kinases, thus promoting increased phosphorylation of CRTC2 and association with 14-3-3 (not shown). At the same time, Akt also directly phosphorylates critical residues of FoxO1 (see the text for details), turning off the transcription of hepatic gluconeogenesis. Transcriptional repressors for hepatic gluconeogenesis such as SHP, DAX-1, and TCF7L2 are induced under this condition, which helps to ensure the inactivation of transcription for gluconeogenic genes as well as PGC-1α.


TCF7L2 is a member of the LEF/TCF family of transcription factors with an HMG-box-type DNA-binding domain, and was shown as a nuclear transcription factor for the well-known Wnt/β-catenin signaling pathway (75-78). Wnt-mediated cellular signaling promotes the nuclear entry of β-catenin, a transcriptional co-activator of TCF7L2, leading to the activation of TCF7L2 target gene transcription. The TCF7L2 signaling pathway was linked to the developmental processes and proliferation events of cancer cells or stem cells (79).

Recently, TCF7L2 has been genetically linked to diabetes, and several human single nucleotide polymorphisms (SNPs) have been identified within the allele of TCF7L2 and correlate with increases in the incidence of this disease (80-84). Recent studies also revealed that TCF7L2 can promote insulin secretion in vivo, either by enhancing the secretion of GLP-1 in the intestinal endocrine L cells or mediating GLP-1-dependent insulin secretion in the pancreatic β cells (85).

The functional role of TCF7L2 as a transcriptional repressor for hepatic glucose metabolism was recently described (22,86). Under feeding conditions, increased TCF7L2 binds to the regulatory elements near CRE and IRE, thereby inhibiting the occupancies of CREB and FoxO1 over the gluconeogenic promoters. This leads to the inhibition of hepatic gluconeogenesis under feeding conditions, which can be mimicked by the overexpression of TCF7L2 in the mouse liver. Under insulin-resistant conditions, however, the expression of medium and short isoforms of TCF7L2, which are exclusively found in the nucleus, are selectively decreased, suggesting that failure to inhibit CREB/FoxO1-dependent gluconeogenesis could occur. Corroborating this hypothesis, we also found that the depletion of TCF7L2 by RNA interference or genetic knockout results in hyperglycemia due to the reduction in hepatic gluconeogenesis. These data suggest that TCF7L2 is critical in the regulation of CREB- and FoxO1-dependent gluconeogenesis in both physiological and pathological conditions. Further study is necessary to determine whether a similar inhibitory loop is present in other TCF7L2-expressing tissues.



In this review, we attempted to summarize the role of two major transcription factors for hepatic gluconeogenesis, CREB and FoxO1 (Fig. 1). Under fasting conditions, the increase in the secretion of glucagon results in the activation of cAMP signaling pathway in the liver, leading to the activation of CREB-dependent as well as CBP/p300- and CRTC2-dependent (its co-activators) transcriptional activation of gluconeogenic genes. Interestingly, some of the important transcriptional regulators themselves are also transcriptionally induced (e.g. PGC-1α, ERRγ), amplifying the magnitude of the gluconeogenic response. FoxO1 is also induced under fasting conditions, in part due to the lack of insulin/Akt pathway in the liver. The transcriptional activity of FoxO1 is greatly enhanced with its co-activator PGC-1α, suggesting that this pathway could be more critical in the later phase of the adaptive response to fasting. Under feeding conditions, the termination of hepatic gluconeogenesis is achieved by inhibition of these transcriptional machineries. The direct role of anabolic hormone insulin by Akt-dependent modification of FoxO1 is well described. Enhanced expression of transcriptional repressors under feeding conditions such as SHP or TCF7L2 also contributes greatly to effectively turning off the hepatic gluconeogenesis. The generation of liver-specific knockout mice for each transcriptional regulators is necessary to delineate the complex transcriptional regulatory mechanisms for hepatic gluconeogenesis in the future.


Supported by : National Research Foundation of Korea (NRF)


  1. Nordlie, R. C., Foster, J. D. and Lange, A. J. (1999) Regulation of glucose production by the liver. Annu. Rev. Nutr. 19, 379-406.
  2. Pilkis, S. J., el-Maghrabi, M. R. and Claus, T. H. (1988) Hormonal regulation of hepatic gluconeogenesis and glycolysis. Annu. Rev. Biochem. 57, 755-783.
  3. Pilkis, S. J. and Claus, T. H. (1991) Hepatic gluconeogenesis/glycolysis: regulation and structure/function relationships of substrate cycle enzymes. Annu. Rev. Nutr. 11, 465-515.
  4. Towle, H. C., Kaytor, E. N. and Shih, H. M. (1997) Regulation of the expression of lipogenic enzyme genes by carbohydrate. Annu. Rev. Nutr. 17, 405-433.
  5. Brown, M. S. and Goldstein, J. L. (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 7, 95-96.
  6. Postic, C., Dentin, R., Denechaud, P. D. and Girard, J. (2007) ChREBP, a transcriptional regulator of glucose and lipid metabolism. Annu. Rev. Nutr. 27, 179-192.
  7. Uyeda, K. and Repa, J. J. (2006) Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab. 4, 107-110.
  8. Moore, M. C., Connolly, C. C. and Cherrington, A. D. (1998) Autoregulation of hepatic glucose production. Eur. J. Endocrinol. 138, 240-248.
  9. Saltiel, A. R. and Kahn, C. R. (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799-806.
  10. Herzig, S., Long, F., Jhala, U. S., Hedrick, S., Quinn, R., Bauer, A., Rudolph, D., Schutz, G., Yoon, C., Puigserver, P., Spiegelman, B. and Montminy, M. (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179-183.
  11. Kim, D. K., Ryu, D., Koh, M., Lee, M. W., Lim, D., Kim, M. J., Kim, Y. H., Cho, W. J., Lee, C. H., Park, S. B., Koo, S. H. and Choi, H. S. (2012) Orphan nuclear receptor estrogen-related receptor gamma (ERRgamma) is key regulator of hepatic gluconeogenesis. J. Biol. Chem. 287, 21628-21639.
  12. Lee, M. W., Chanda, D., Yang, J., Oh, H., Kim, S. S., Yoon, Y. S., Hong, S., Park, K. G., Lee, I. K., Choi, C. S., Hanson, R. W., Choi, H. S. and Koo, S. H. (2010) Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH. Cell Metab. 11, 331-339.
  13. van Schaftingen, E. and Gerin, I. (2002) The glucose-6-phosphatase system. Biochem. J. 362, 513-532.
  14. Bedford, D. C., Kasper, L. H., Wang, R., Chang, Y., Green, D. R. and Brindle, P. K. (2011) Disrupting the CH1 domain structure in the acetyltransferases CBP and p300 results in lean mice with increased metabolic control. Cell Metab. 14, 219-230.
  15. Choi, D., Oh, K. J., Han, H. S., Yoon, Y. S., Jung, C. Y., Kim, S. T. and Koo, S. H. (2012) Protein arginine methyltransferase 1 regulates hepatic glucose production in a FoxO1-dependent manner. Hepatology. 56, 1546-1556.
  16. Koo, S. H., Flechner, L., Qi, L., Zhang, X., Screaton, R. A., Jeffries, S., Hedrick, S., Xu, W., Boussouar, F., Brindle, P., Takemori, H. and Montminy, M. (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109-1111.
  17. Krones-Herzig, A., Mesaros, A., Metzger, D., Ziegler, A., Lemke, U., Bruning, J. C. and Herzig, S. (2006) Signal-dependent control of gluconeogenic key enzyme genes through coactivator-associated arginine methyltransferase 1. J. Biol. Chem. 281, 3025-3029.
  18. Puigserver, P., Rhee, J., Donovan, J., Walkey, C. J., Yoon, J. C., Oriente, F., Kitamura, Y., Altomonte, J., Dong, H., Accili, D. and Spiegelman, B. M. (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423, 550-555.
  19. Yoon, J. C., Puigserver, P., Chen, G., Donovan, J., Wu, Z., Rhee, J., Adelmant, G., Stafford, J., Kahn, C. R., Granner, D. K., Newgard, C. B. and Spiegelman, B. M. (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131-138.
  20. Lee, J. M., Seo, W. Y., Song, K. H., Chanda, D., Kim, Y. D., Kim, D. K., Lee, M. W., Ryu, D., Kim, Y. H., Noh, J. R., Lee, C. H., Chiang, J. Y., Koo, S. H. and Choi, H. S. (2010) AMPK-dependent repression of hepatic gluconeogenesis via disruption of CREB.CRTC2 complex by orphan nuclear receptor small heterodimer partner. J. Biol. Chem. 285, 32182-32191.
  21. Nedumaran, B., Hong, S., Xie, Y. B., Kim, Y. H., Seo, W. Y., Lee, M. W., Lee, C. H., Koo, S. H. and Choi, H. S. (2009) DAX-1 acts as a novel corepressor of orphan nuclear receptor HNF4alpha and negatively regulates gluconeogenic enzyme gene expression. J. Biol. Chem. 284, 27511-27523.
  22. Oh, K. J., Park, J., Kim, S. S., Oh, H., Choi, C. S. and Koo, S. H. (2012) TCF7L2 modulates glucose homeostasis by regulating CREB- and FoxO1-dependent transcriptional pathway in the liver. PloS. Genetics. 8, e1002986.
  23. Gonzalez, G. A. and Montminy, M. R. (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 59, 675-680.
  24. Arias, J., Alberts, A. S., Brindle, P., Claret, F. X., Smeal, T., Karin, M., Feramisco, J. and Montminy, M. (1994) Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370, 226-229.
  25. Chrivia, J. C., Kwok, R. P., Lamb, N., Hagiwara, M., Montminy, M. R. and Goodman, R. H. (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365, 855-859.
  26. Kwok, R. P., Lundblad, J. R., Chrivia, J. C., Richards, J. P., Bachinger, H. P., Brennan, R. G., Roberts, S. G., Green, M. R. and Goodman, R. H. (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370, 223-226.
  27. Conkright, M. D., Guzman, E., Flechner, L., Su, A. I., Hogenesch, J. B. and Montminy, M. (2003) Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. Mol. Cell. 11, 1101-1108.
  28. Iourgenko, V., Zhang, W., Mickanin, C., Daly, I., Jiang, C., Hexham, J. M., Orth, A. P., Miraglia, L., Meltzer, J., Garza, D., Chirn, G. W., McWhinnie, E., Cohen, D., Skelton, J., Terry, R., Yu, Y., Bodian, D., Buxton, F. P., Zhu, J., Song, C. and Labow, M. A. (2003) Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells. Proc. Natl. Acad. Sci. U. S. A. 100, 12147-12152.
  29. Alberts, A. S., Arias, J., Hagiwara, M., Montminy, M. R. and Feramisco, J. R. (1994) Recombinant cyclic AMP response element binding protein (CREB) phosphorylated on Ser-133 is transcriptionally active upon its introduction into fibroblast nuclei. J. Biol. Chem. 269, 7623-7630.
  30. Wadzinski, B. E., Wheat, W. H., Jaspers, S., Peruski, L. F. Jr., Lickteig, R. L., Johnson, G. L. and Klemm, D. J. (1993) Nuclear protein phosphatase 2A dephosphorylates protein kinase A-phosphorylated CREB and regulates CREB transcriptional stimulation. Mol. Cell. Biol. 13, 2822-2834.
  31. Hanson, R. W. and Reshef, L. (1997) Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu. Rev. Biochem. 66, 581-611.
  32. Erion, D. M., Ignatova, I. D., Yonemitsu, S., Nagai, Y., Chatterjee, P., Weismann, D. Hsiao, J. J., Zhang, D., Iwasaki, T., Stark, R., Flannery, C., Kahn, M., Carmean, C. M., Yu, X. X., Murray, S. F., Bhanot, S., Monia, B. P., Cline, G. W., Samuel, V. T. and Shulman, G. I. (2009) Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein. Cell Metab. 10, 499-506.
  33. Bannister, A. J. and Kouzarides, T. (1996) The CBP co-activator is a histone acetyltransferase. Nature 384, 641-643.
  34. Ogryzko, V. V., Schiltz, R. L., Russanova, V., Howard, B. H. and Nakatani, Y. (1996) The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 87, 953-959.
  35. Tanaka, Y., Naruse, I., Maekawa, T., Masuya, H., Shiroishi, T. and Ishii, S. (1997) Abnormal skeletal patterning in embryos lacking a single Cbp allele: a partial similarity with Rubinstein-Taybi syndrome. Proc. Natl. Acad. Sci. U. S. A. 94, 10215-10220.
  36. Yao, T. P., Oh, S. P., Fuchs, M., Zhou, N. D., Ch'ng, L. E., Newsome, D., Bronson, R. T., Li, E., Livingston, D. M. and Eckner, R. (1998) Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300. Cell. 93, 361-372.
  37. Yamauchi, T., Oike, Y., Kamon, J., Waki, H., Komeda, K., Tsuchida, A., Date, Y., Li, M. X., Miki, H., Akanuma, Y., Nagai, R., Kimura, S., Saheki, T., Nakazato, M., Naitoh, T., Yamamura, K. and Kadowaki, T. (2002) Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nat. Genet. 30, 221-226.
  38. He, L., Sabet, A., Djedjos, S., Miller, R., Sun, X., Hussain, M. A., Radovick, S. and Wondisford, F. E. (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell. 137, 635-646.
  39. Dentin, R., Girard, J. and Postic, C. (2005) Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie. 87, 81-86.
  40. Altarejos, J. Y. and Montminy, M. (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat. Rev. Mol. Cell Biol. 12, 141-151.
  41. Yoon, Y. S., Lee, M. W., Ryu, D., Kim, J. H., Ma, H., Seo, W. Y., Kim, Y. N., Kim, S. S., Lee, C. H., Hunter, T., Choi, C. S., Montminy, M. R. and Koo, S. H. (2010) Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis. Proc. Natl. Acad. Sci. U.S.A. 107, 17704-17709.
  42. Wang, Y., Li, G., Goode, J., Paz, J. C., Ouyang, K., Screaton, R., Fischer, W. H., Chen, J., Tabas, I. and Montminy, M. (2012) Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485, 128-132.
  43. Yoon, Y. S., Ryu, D., Lee, M. W., Hong, S. and Koo, S. H. (2009) Adiponectin and thiazolidinedione targets CRTC2 to regulate hepatic gluconeogenesis. Exp. Mol. Med. 41, 577-583.
  44. Saberi, M., Bjelica, D., Schenk, S., Imamura, T., Bandyopadhyay, G., Li, P., Vargeese, C., Wang, W., Bowman, K., Zhang, Y., Polisky, B. and Olefsky, J. M. (2009) Novel liver-specific TORC2 siRNA corrects hyperglycemia in rodent models of type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 297, E1137-1146.
  45. Wang, Y., Inoue, H., Ravnskjaer, K., Viste, K., Miller, N., Liu, Y., Hedrick, S., Vera, L. and Montminy, M. (2010) Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Proc. Natl. Acad. Sci. U. S. A. 107, 3087-3092.
  46. Wang, Y., Vera, L., Fischer, W. H. and Montminy, M. (2009) The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460, 534-537.
  47. Ryu, D., Oh, K. J., Jo, H. Y., Hedrick, S., Kim, Y. N., Hwang, Y. J., Park, T. S., Han, J. S., Choi, C. S., Montminy M. and Koo, S. H. (2009) TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1. Cell Metab. 9, 240-251.
  48. Accili, D. and Arden, K. C. (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421-426.
  49. Barthel, A., Schmoll, D. and Unterman, T. G. (2005) FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16, 183-189.
  50. Biggs, W. H., 3rd, Meisenhelder, J., Hunter, T., Cavenee, W. K. and Arden, K. C. (1999) Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl. Acad. Sci. U. S. A. 96, 7421-7426.
  51. Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J. and Greenberg, M. E. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 96, 857-868.
  52. Nakae, J., Park, B. C. and Accili, D. (1999) Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J. Biol. Chem. 274, 15982-15985.
  53. Daitoku, H., Hatta, M., Matsuzaki, H., Aratani, S., Ohshima, T., Miyagishi, M., Nakajima, T. and Fukamizu, A. (2004) Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc. Natl. Acad. Sci. U. S. A. 101, 10042-10047.
  54. Motta, M. C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M. and Guarente, L. (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell. 116, 551-563.
  55. van der Horst, A., Tertoolen, L. G., de Vries-Smits, L. M., Frye, R. A., Medema, R. H. and Burgering, B. M. (2004) FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J. Biol. Chem. 279, 28873-28879.
  56. Haeusler, R. A., Kaestner, K. H. and Accili, D. (2010) FoxOs function synergistically to promote glucose production. J. Biol. Chem. 285, 35245-35248.
  57. Ayala, J. E., Streeper, R. S., Desgrosellier, J. S., Durham, S. K., Suwanichkul, A., Svitek, C. A., Goldman, J. K., Barr, F. G., Powell, D. R. and O'Brien, R. M. (1999) Conservation of an insulin response unit between mouse and human glucose-6-phosphatase catalytic subunit gene promoters: transcription factor FKHR binds the insulin response sequence. Diabetes. 48, 1885-1889.
  58. Matsumoto, M., Pocai, A., Rossetti, L., Depinho, R. A. and Accili, D. (2007) Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab. 6, 208-216.
  59. Kim, D. H., Perdomo, G., Zhang, T., Slusher, S., Lee, S., Phillips, B. E., Fan, Y., Giannoukakis, N., Gramignoli, R., Strom, S., Ringquist, S. and Dong, H. H. (2011) FoxO6 integrates insulin signaling with gluconeogenesis in the liver. Diabetes. 60, 2763-2774.
  60. Puigserver, P., Wu, Z., Park, C. W., Graves, R., Wright, M. and Spiegelman, B. M. (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 92, 829-839.
  61. Puigserver, P., Adelmant, G., Wu, Z., Fan, M., Xu, J., O'Malley, B. and Spiegelman, B. M. (1999) Activation of PPARgamma coactivator-1 through transcription factor docking. Science 286, 1368-1371.
  62. Wallberg, A. E., Yamamura, S., Malik, S., Spiegelman, B. M. and Roeder, R. G. (2003) Coordination of p300-mediated chromatin remodeling and TRAP/mediator function through coactivator PGC-1alpha. Mol. Cell. 12, 1137-1149.
  63. Lin, J., Handschin, C. and Spiegelman, B. M. (2005) Metabolic control through the PGC-1 family of transcription coactivators. Cell. Metab. 1, 361-370.
  64. Huang, Z. M., Wu, J., Jia, Z. C., Tian, Y., Tang, J., Tang, Y., Wang, Y., Wu, Y. Z. and Ni, B. (2012) Identification of interacting proteins of retinoid-related orphan nuclear receptor gamma in HepG2 cells. BMB Rep. 45, 331-336.
  65. Koo, S. H., Satoh, H., Herzig, S., Lee, C. H., Hedrick, S., Kulkarni, R., Evans, R. M., Olefsky, J. and Montminy, M. (2004) PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat. Med. 10, 530-534.
  66. Lin, 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., Cui, L., Manieri, M., Donovan, M. X., Wu, Z., Cooper, M. P., Fan, M. C., Rohas, L. M., Zavacki, A. M., Cinti, S., Shulman, G. I., Lowell, B. B., Krainc, D. and Spiegelman, B. M. (2004) Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 119, 121-135.
  67. Choi, D., Oh, K. J. and Koo, S. H. (2013) Protein arginine methylation in hepatic glucose metabolism regulation: Histone or nonhistone? That is the question. Reply. Hepatology. 57, 2091.
  68. Takahashi, Y., Daitoku, H., Hirota, K., Tamiya, H., Yokoyama, A., Kako, K., Nagashima, Y., Nakamura, A., Shimada, T., Watanabe, S., Yamagata, K., Yasuda, K., Ishii, N. and Fukamizu, A. (2011) Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16. Cell Metab. 13, 505-516.
  69. Yamagata, K., Daitoku, H., Takahashi, Y., Namiki, K., Hisatake, K., Kako, K., Mukai, H., Kasuya, Y. and Fukamizu, A. (2008) Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol. Cell. 32, 221-231.
  70. Iyer, A. K. and McCabe, E. R. (2004) Molecular mechanisms of DAX1 action. Mol. Genet. Metab. 83, 60-73.
  71. Seol, W., Choi, H. S. and Moore, D. D. (1996) An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272, 1336-1339.
  72. Chanda, D., Park, J. H. and Choi, H. S. (2008) Molecular basis of endocrine regulation by orphan nuclear receptor Small Heterodimer Partner. Endocr. J. 55, 253-268.
  73. Lee, Y. S., Chanda, D., Sim, J., Park, Y. Y. and Choi, H. S. (2007) Structure and function of the atypical orphan nuclear receptor small heterodimer partner. Int. Rev. Cytol. 261, 117-158.
  74. Kim, Y. D., Park, K. G., Lee, Y. S., Park, Y. Y., Kim, D. K., Nedumaran, B., Jang, W. G., Cho, W. J., Ha, J., Lee, I. K., Lee, C. H. and Choi, H. S. (2008) Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 57, 306-314.
  75. Behrens, J., von Kries, J. P., Kuhl, M., Bruhn, L., Wedlich, D., Grosschedl, R. and Birchmeier W. (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382, 638-642.
  76. Huber, O., Korn, R., McLaughlin, J., Ohsugi, M., Herrmann, B. G. and Kemler, R. (1996) Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech. Dev. 59, 3-10.
  77. Molenaar, M., van de Wetering, M., Oosterwegel, M., Peterson-Maduro, J., Godsave, S., Korinek, V., Roose, J., Destree, O. and Clevers, H. (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86, 391-399.
  78. Rubinfeld, B., Robbins, P., El-Gamil, M., Albert, I., Porfiri, E. and Polakis, P. (1997) Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 275, 1790-1792.
  79. Clevers, H. (2006) Wnt/beta-catenin signaling in development and disease. Cell 127, 469-480.
  80. Chandak, G. R., Janipalli, C. S., Bhaskar, S., Kulkarni, S. R., Mohankrishna, P., Hattersley, A. T., Frayling, T. M. and Yajnik, C. S. (2007) Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 50, 63-67.
  81. Grant, S. F., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Manolescu, A., Sainz, J., Helgason, A., Stefansson, H., Emilsson, V., Helgadottir, A., Styrkarsdottir, U., Magnusson, K. P., Walters, G. B., Palsdottir, E., Jonsdottir, T., Gudmundsdottir, T., Gylfason, A., Saemundsdottir, J., Wilensky, R. L., Reilly, M. P., Rader, D. J., Bagger, Y., Christiansen, C., Gudnason, V., Sigurdsson, G., Thorsteinsdottir, U., Gulcher, J. R., Kong, A. and Stefansson, K. (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 38, 320-323.
  82. Hayashi, T., Iwamoto, Y., Kaku, K., Hirose, H. and Maeda, S. (2007) Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia 50, 980-984.
  83. Helgason, A., Palsson, S., Thorleifsson, G., Grant, S. F., Emilsson, V., Gunnarsdottir, S., Adeyemo, A., Chen, Y., Chen, G., Reynisdottir, I., Benediktsson, R., Hinney, A., Hansen, T., Andersen, G., Borch-Johnsen, K., Jorgensen, T., Schafer, H., Faruque, M., Doumatey, A., Zhou, J., Wilensky, R. L., Reilly, M. P., Rader, D. J., Bagger, Y., Christiansen, C., Sigurdsson, G., Hebebrand, J., Pedersen, O., Thorsteinsdottir, U., Gulcher, J. R., Kong, A., Rotimi, C. and Stefansson, K. (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat. Genet. 39, 218-225.
  84. Lehman, D. M., Hunt, K. J., Leach, R. J., Hamlington, J., Arya, R., Abboud, H. E., Duggirala, R., Blangero, J., Goring, H. H. and Stern, M. P. (2007) Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans. Diabetes 56, 389-393.
  85. Yi, F., Brubaker, P. L. and Jin, T. (2005) TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J. Biol. Chem. 280, 1457-1464.
  86. Norton, L., Fourcaudot, M., Abdul-Ghani, M. A., Winnier, D., Mehta, F. F., Jenkinson, C. P. and Defronzo, R. A. (2011) Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism. Diabetologia 54, 3132-3142.

Cited by

  1. RA abrogates hepatic gluconeogenesis and insulin resistance by enhancing IRS-1 and AMPK signalling in experimental type 2 diabetes vol.5, pp.55, 2015,
  2. Association of PCK1 with Body Mass Index and Other Metabolic Features in Patients With Psychotropic Treatments vol.35, pp.5, 2015,
  3. Nemo-like kinase as a negative regulator of nuclear receptor Nurr1 gene transcription in prostate cancer vol.16, pp.1, 2016,
  4. Chronic central leptin infusion modulates the glycemia response to insulin administration in male rats through regulation of hepatic glucose metabolism vol.415, 2015,
  5. Exploring the emerging complexity in transcriptional regulation of energy homeostasis vol.16, pp.11, 2015,
  6. Contrasting Patterns in the Evolution of Vertebrate MLX Interacting Protein (MLXIP) and MLX Interacting Protein-Like (MLXIPL) Genes vol.11, pp.2, 2016,
  7. Crystal structures reveal a new and novel FoxO1 binding site within the human glucose-6-phosphatase catalytic subunit 1 gene promoter vol.198, pp.1, 2017,
  8. Constitutive photomorphogenesis protein 1 (COP1) and COP9 signalosome, evolutionarily conserved photomorphogenic proteins as possible targets of melatonin vol.61, pp.1, 2016,
  9. Hepatic estrogen receptor α is critical for regulation of gluconeogenesis and lipid metabolism in males vol.7, pp.1, 2017,
  10. A decrease in hepatic microRNA-9 expression impairs gluconeogenesis by targeting FOXO1 in obese mice vol.59, pp.7, 2016,
  11. MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4 vol.290, pp.13, 2015,
  12. Diminished Phosphorylation of CREB Is a Key Event in the Dysregulation of Gluconeogenesis and Glycogenolysis in PCB126 Hepatotoxicity vol.29, pp.9, 2016,
  13. Associations between Forkhead Box O1 (FoxO1) Expression and Indicators of Hepatic Glucose Production in Transition Dairy Cows Supplemented with Dietary Nicotinic Acid vol.11, pp.1, 2016,
  14. Growth hormone abolishes beneficial effects of calorie restriction in long-lived Ames dwarf mice vol.58, 2014,
  15. Tunable regulation of CREB DNA binding activity couples genotoxic stress response and metabolism 2016,
  16. Opposite effects of β 2 -adrenoceptor gene deletion on insulin signaling in liver and skeletal muscle vol.27, pp.7, 2017,
  17. Dendrobium nobile Lindl. alkaloids regulate metabolism gene expression in livers of mice vol.69, pp.10, 2017,
  18. MicroRNA-451 Negatively Regulates Hepatic Glucose Production and Glucose Homeostasis by Targeting Glycerol Kinase–Mediated Gluconeogenesis vol.65, pp.11, 2016,
  19. Effect of brain-derived neurotrophic factor (BDNF) on hepatocyte metabolism vol.88, 2017,
  20. (−)-Epicatechin-3-O-β-D-allopyranoside from Davallia formosana prevents diabetes and dyslipidemia in streptozotocin-induced diabetic mice vol.12, pp.3, 2017,
  21. Exploiting human and mouse transcriptomic data: Identification of circadian genes and pathways influencing health vol.37, pp.5, 2015,
  22. Benzylglucosinolate Derived Isothiocyanate from Tropaeolum majus Reduces Gluconeogenic Gene and Protein Expression in Human Cells vol.11, pp.9, 2016,
  23. A global perspective on FOXO1 in lipid metabolism and lipid-related diseases vol.66, 2017,
  24. The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis vol.65, pp.5, 2017,
  25. Regulation of glucose metabolism from a liver-centric perspective vol.48, pp.3, 2016,
  26. SREBP1c-CRY1 signalling represses hepatic glucose production by promoting FOXO1 degradation during refeeding vol.7, 2016,
  27. Understanding how long-acting β2-adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma - an update vol.173, pp.24, 2016,
  28. Pregnane X Receptor (PXR)-Mediated Gene Repression and Cross-Talk of PXR with Other Nuclear Receptors via Coactivator Interactions vol.7, 2016,
  29. Bisphenol S exposure impairs glucose homeostasis in male zebrafish ( Danio rerio ) vol.147, 2018,
  30. HNF-4α regulated miR-122 contributes to development of gluconeogenesis and lipid metabolism disorders in Type 2 diabetic mice and in palmitate-treated HepG2 cells vol.791, 2016,
  31. Transcriptional regulatory logic of the diurnal cycle in the mouse liver vol.15, pp.4, 2017,
  32. Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus vol.6, pp.12, 2016,
  33. Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology vol.23, pp.13, 2014,
  34. The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells vol.382, pp.2, 2016,
  35. ATF-2/CREB/IRF-3-targeted anti-inflammatory activity of Korean red ginseng water extract vol.154, pp.1, 2014,
  36. Phenolic compounds isolated from fermented blueberry juice decrease hepatocellular glucose output and enhance muscle glucose uptake in cultured murine and human cells vol.17, pp.1, 2017,
  37. Neuregulin 1 Improves Glucose Tolerance in db/db Mice vol.10, pp.7, 2015,
  38. The Impact of Intramammary Escherichia coli Challenge on Liver and Mammary Transcriptome and Cross-Talk in Dairy Cows during Early Lactation Using RNAseq vol.11, pp.6, 2016,
  39. Glutamine dipeptide and cortisol change the liver glucose metabolism and reduce the severity of insulin-induced hypoglycaemia in untreated T1DM Swiss mice vol.123, pp.2, 2017,
  40. Eburicoic Acid, a Triterpenoid Compound from Antrodia camphorata, Displays Antidiabetic and Antihyperlipidemic Effects in Palmitate-Treated C2C12 Myotubes and in High-Fat Diet-Fed Mice vol.18, pp.11, 2017,
  41. Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis vol.67, pp.4, 2018,
  42. 4-hydroxy-3-methoxycinnamic acid regulates orexigenic peptides and hepatic glucose homeostasis through phosphorylation of FoxO1 vol.50, pp.2, 2018,
  43. Long noncoding RNA Gomafu upregulates Foxo1 expression to promote hepatic insulin resistance by sponging miR-139-5p vol.9, pp.3, 2018,
  44. FAM3B (PANDER) functions as a co-activator of FOXO1 to promote gluconeogenesis in hepatocytes pp.15821838, 2018,
  45. Long non-coding RNA H19 inhibition promotes hyperglycemia in mice by upregulating hepatic FoxO1 levels and promoting gluconeogenesis pp.1432-1440, 2018,
  46. Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling vol.9, pp.1663-9812, 2018,
  47. Epigallocatechin gallate suppresses hepatic cholesterol synthesis by targeting SREBP-2 through SIRT1/FOXO1 signaling pathway vol.448, pp.1-2, 2018,
  48. Hepatic leukocyte immunoglobulin-like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1-TRAF6 pathway vol.67, pp.4, 2018,
  49. Dexamethasone Administration During Late Gestation Has No Major Impact on Lipid Metabolism, but Reduces Newborn Survival Rate in Wistar Rats vol.9, pp.1664-042X, 2018,
  50. Exposure to 2,4-dichlorophenoxyacetic acid induced PPARβ-dependent disruption of glucose metabolism in HepG2 cells vol.25, pp.17, 2018,
  51. Discovery of pancreastatin inhibitor PSTi8 for the treatment of insulin resistance and diabetes: studies in rodent models of diabetes mellitus vol.8, pp.1, 2018,
  52. , by regulation of Akt phosphorylation, gluconeogenesis, and PPARα in streptozotocin-induced diabetic mice vol.8, pp.37, 2018,
  53. p300/CBP as a Key Nutritional Sensor for Hepatic Energy Homeostasis and Liver Fibrosis vol.2018, pp.2314-6141, 2018,
  54. Systemic bile acids induce insulin resistance in a TGR5-independent manner pp.1522-1555, 2019,