Key points are not available for this paper at this time.
Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by glucagon, which is elevated in the blood during fasting and in diabetes. In this study, we have shown that p38 mitogen-activated protein kinase (p38) was activated in liver by fasting and in primary hepatocytes by glucagon or forskolin. Fasting plasma glucose levels were reduced upon blockade of p38 with either a chemical inhibitor or small interference RNA in mice. In examining the mechanism, inhibition of p38 suppressed gluconeogenesis in liver, along with expression of key gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Peroxisome proliferator-activated receptor γ coactivator 1α and cAMP-response element-binding protein have been shown to be important mediators of hepatic gluconeogenesis. We have shown that inhibition of p38 prevented transcription of the PPARγ coactivator 1α gene as well as phosphorylation of cAMP-response element-binding protein. Together, our results from in vitro and in vivo studies define a model in which cAMP-dependent activation of genes involved in gluconeogenesis is dependent upon the p38 pathway, thus adding a new player to our evolving understanding of this physiology. Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by glucagon, which is elevated in the blood during fasting and in diabetes. In this study, we have shown that p38 mitogen-activated protein kinase (p38) was activated in liver by fasting and in primary hepatocytes by glucagon or forskolin. Fasting plasma glucose levels were reduced upon blockade of p38 with either a chemical inhibitor or small interference RNA in mice. In examining the mechanism, inhibition of p38 suppressed gluconeogenesis in liver, along with expression of key gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Peroxisome proliferator-activated receptor γ coactivator 1α and cAMP-response element-binding protein have been shown to be important mediators of hepatic gluconeogenesis. We have shown that inhibition of p38 prevented transcription of the PPARγ coactivator 1α gene as well as phosphorylation of cAMP-response element-binding protein. Together, our results from in vitro and in vivo studies define a model in which cAMP-dependent activation of genes involved in gluconeogenesis is dependent upon the p38 pathway, thus adding a new player to our evolving understanding of this physiology. Gluconeogenesis in the liver is the process of de novo synthesis of glucose from non-hexose carbohydrate precursors such as lactate, pyruvate, alanine, and glycerol. This process plays a key role in maintaining blood glucose concentrations within a very narrow range during fasting (1Pilkis S.J. Granner D.K. Annu. Rev. Physiol. 1992; 54: 885-909Crossref PubMed Scopus (706) Google Scholar, 2Nordlie R.C. Foster J.D. Lange A.J. Annu. Rev. Nutr. 1999; 19: 379-406Crossref PubMed Scopus (434) Google Scholar). Gluconeogenesis is largely controlled by the balance between insulin and glucagon. In the fed state, plasma insulin levels are increased while glucagon levels are decreased (2Nordlie R.C. Foster J.D. Lange A.J. Annu. Rev. Nutr. 1999; 19: 379-406Crossref PubMed Scopus (434) Google Scholar, 3Berg J. Tymoczko J. Stryer L. Biochemistry. W. H. Freeman and Company, New York2001: 845-866Google Scholar, 4Accili D. Diabetes. 2004; 53: 1633-1642Crossref PubMed Scopus (149) Google Scholar). Insulin propels glucose uptake into peripheral tissues such as muscle and adipose tissue while serving as a brake to stop hepatic gluconeogenesis (3Berg J. Tymoczko J. Stryer L. Biochemistry. W. H. Freeman and Company, New York2001: 845-866Google Scholar, 5Mittelman S.D. Fu Y.Y. Rebrin K. Steil G. Bergman R.N. J. Clin. Investig. 1997; 100: 3121-3130Crossref PubMed Scopus (87) Google Scholar, 6Granner D. Andreone T. Sasaki K. Beale E. Nature. 1983; 305: 549-551Crossref PubMed Scopus (246) Google Scholar, 7O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (438) Google Scholar, 8Massillon D. Barzilai N. Chen W. Hu M. Rossetti L. J. Biol. Chem. 1996; 271: 9871-9874Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar, 9Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (633) Google Scholar). In contrast, in the fasted state insulin levels are diminished while glucagon levels are increased, leading to elevation of gluconeogenesis. In diabetes, the ability of insulin to suppress gluconeogenesis is lost due to absolute insulin deficiency in type I diabetes or is severely compromised in type II diabetes due to insulin resistance and relative insufficiency of insulin production. As a result, hepatic gluconeogenesis becomes the major contributor to postprandial and fasting hyperglycemia in both forms of diabetes (see Refs. 3Berg J. Tymoczko J. Stryer L. Biochemistry. W. H. Freeman and Company, New York2001: 845-866Google Scholar and 4Accili D. Diabetes. 2004; 53: 1633-1642Crossref PubMed Scopus (149) Google Scholar for review). Gluconeogenesis is a classic cAMP/protein kinase A (PKA) 3The abbreviations used are: PKAprotein kinase APEPCKphosphoenolpyruvate carboxykinaseG6Paseglucose-6-phosphataseCREcAMP-response elementCREBCRE-binding proteinsiRNAsmall interference RNAHGPhepatic glucose productionSBSB203580.-dependent process initiated by glucagon (see Ref. 9Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (633) Google Scholar for review). Although the molecular mechanism(s) that are responsible for the elevation of hepatic gluconeogenesis in diabetes have been extensively studied, much remains unresolved (reviewed in Ref. 4Accili D. Diabetes. 2004; 53: 1633-1642Crossref PubMed Scopus (149) Google Scholar). It is generally understood that the increase of gluconeogenesis in diabetes is due to the unrestrained expression and activity of gluconeogenic enzymes (see Refs. 3Berg J. Tymoczko J. Stryer L. Biochemistry. W. H. Freeman and Company, New York2001: 845-866Google Scholar and 4Accili D. Diabetes. 2004; 53: 1633-1642Crossref PubMed Scopus (149) Google Scholar for reviews). Normally, insulin can inhibit gluconeogenesis through multiple mechanisms. First, in the pancreas insulin inhibits glucagon secretion from α-cells so as to promptly eliminate the dominant stimulator of gluconeogenesis (reviewed in Ref. 4Accili D. Diabetes. 2004; 53: 1633-1642Crossref PubMed Scopus (149) Google Scholar). Second, in the liver insulin blocks the glucagon signaling mechanism by activating a cAMP phosphodiesterase. Third, insulin can directly suppress the transcription of key gluconeogenic genes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Specifically, insulin blocks the recruitment of the transcriptional coactivators PGC-1α and CREB-binding protein to the promoters of the PEPCK and G6Pase genes (10Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. Spiegelman B. Montminy M. Nature. 2001; 413: 179-183Crossref PubMed Scopus (1134) Google Scholar). As a result, the transcription of gluconeogenic genes is strongly inhibited by insulin. Because insulin action is deficient in diabetes, all these suppressive mechanisms are lost, and as a consequence the stimulatory machinery of gluconeogenesis is activated. These include the cAMP/PKA-dependent expression of the PGC-1α gene, in addition to PEPCK and G6Pase (11Yoon 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. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1515) Google Scholar, 12Koo S.H. Satoh H. Herzig S. Lee C.H. Hedrick S. Kulkarni R. Evans R.M. Olefsky J. Montminy M. Nat. Med. 2004; 10: 530-534Crossref PubMed Scopus (478) Google Scholar). However, the cascade of signaling events downstream of PKA, including the possible role of other kinases, has not been explored. protein kinase A phosphoenolpyruvate carboxykinase glucose-6-phosphatase cAMP-response element CRE-binding protein small interference RNA hepatic glucose production SB203580. We and others have previously shown that p38 is a downstream effector of PKA (13Cao W. Medvedev A.V. Daniel K.W. Collins S. J. Biol. Chem. 2001; 276: 27077-27082Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 14Mizuno K. Kanda Y. Kuroki Y. Nishio M. Watanabe Y. Br. J. Pharmacol. 2002; 135: 951-960Crossref PubMed Scopus (19) Google Scholar, 15Schulte G. Fredholm B.B. Exp. Cell. Res. 2003; 290: 168-176Crossref PubMed Scopus (83) Google Scholar, 16Cao W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar, 17Robidoux J. Cao W.H. Quan Q. Daniel K.W. Moukdar F. Bai B. Floering L.M. Collins S. Mol. Cell. Biol. 2005; 25: 5466-5479Crossref PubMed Scopus (92) Google Scholar). More recently, we identified p38 as necessary for the control of energy balance by mediating PKA-dependent transcription of brown fat thermogenic genes, such as uncoupling protein 1 (UCP1) and PGC-1α (13Cao W. Medvedev A.V. Daniel K.W. Collins S. J. Biol. Chem. 2001; 276: 27077-27082Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 16Cao W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar, 17Robidoux J. Cao W.H. Quan Q. Daniel K.W. Moukdar F. Bai B. Floering L.M. Collins S. Mol. Cell. Biol. 2005; 25: 5466-5479Crossref PubMed Scopus (92) Google Scholar). In this study, we have extended these observations in adipocytes to another metabolically important cell type, hepatocytes. Our results identify p38 as a component in the signaling mechanism for cAMP-dependent expression of gluconeogenic genes and hepatic gluconeogenesis. Chemicals and Antibodies—SB203580 (SB) and streptozotocin were from Calbiochem. Forskolin and glucagon were from Sigma. Antibodies against p38 (number 9212; Cell Signaling Technology), phosphorylated p38 (36–8500; Zymed Laboratories Inc.), CREB (9192; Cell Signaling Technology), or phospho-CREB-Ser-133 (9191; Cell Signaling Technology) were purchased. The wild-type and mutant PGC-1α constructs were kind gifts from Dr. Bruce Spiegelman. The PEPCK promoter construct was a kind gift from Dr. Jianhua Shao. Construction of Adenoviral Vector Encoding siRNAs—Adenoviral vector expressing siRNA against p38α was constructed as we previously described (18Bain J.R. Schisler J.C. Takeuchi K. Newgard C.B. Becker T.C. Diabetes. 2004; 53: 2190-2194Crossref PubMed Scopus (69) Google Scholar). Double-stranded DNA oligonucleotides containing specific sequences of p38α (205TACCGAGAGTTGCGTCTGC 224) were prepared by annealing the synthesized sense and antisense oligonucleotides. The sense oligonucleotide (5′-ATCCCCACCGAGAGTTGCGTCTGCTTCAGAGAGCAGACGCACTCTCCGGTATTTTTGGAAA-3′) and complementary antisense oligonucleotide 5′-AGCTTTTCCAAAAAACCGAGAGTTGCGTCTGCTCTCTTGAAGCAGACGCACTCTCCGGTAGGG-3′) were synthesized by Integrated DNA Technologies (IDT). The adenoviral vector encoding the siRNA against p38α was verified by PCR and sequencing. Preparation of Primary Hepatocytes and Viral Infections—Primary hepatocytes were prepared as previously described (19Seglen P.O. J. Toxicol. Environ. Health. 1979; 5: 551-560Crossref PubMed Scopus (113) Google Scholar). Briefly, under anesthesia with pentobarbital (intraperitoneal injection, 30 mg/kg of body weight), were through with in A and for Hepatocytes were and to and The of hepatocytes was by and was Hepatocytes were into in were for and were with or glucagon in the or of as adenoviral were The were prepared in by (18Bain J.R. Schisler J.C. Takeuchi K. Newgard C.B. Becker T.C. Diabetes. 2004; 53: 2190-2194Crossref PubMed Scopus (69) Google Scholar, C. E. T. C. Newgard C.B. Diabetes. 2003; PubMed Scopus Google Scholar). levels of p38 in hepatocytes were by or cell were prepared by and by addition of of were and of phosphorylated and p38 or CREB were with a of specific by a of with were with a and were from and in essential were with as and to PGC-1α and PEPCK promoter with and from these were to the was for the of the to cAMP production. and were as described previously A.V. S. D. Collins S. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus (92) Google or in from RNA and RNA from were prepared RNA from were to from the The for PEPCK and PGC-1α by were from RNA was through and S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). were prepared by in the of to a specific activity of of were and all as previously described S. Daniel K.W. Mol. Google Scholar, S. A. PubMed Scopus Google Scholar). role of p38 in hepatic gluconeogenesis in vivo was in with or diabetes of were used in the were fasted for as of the control were fed was during the mg/kg of body The was the of the and the The and of were in W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar, B. Lee J.C. J. Pharmacol. Exp. 1996; Google Scholar). A model of I diabetes was by of streptozotocin for mg/kg of body Z. A. N. H. S. Y. H. A. R. M. D. Diabetes. 2003; 5: PubMed Scopus Google Scholar). all plasma glucose levels were with a glucose were for protein and RNA of p38 and CREB phosphorylation and expression of and PGC-1α genes in the liver were of Hepatic of were used in the The used has been previously described Z. Full Text PDF PubMed Scopus Google Scholar). Briefly, were fasted for anesthesia with pentobarbital (intraperitoneal injection, 30 mg/kg of body weight), a was into through were to for 30 was was the of the while another was A was by the of for were and glucose levels were with a glucose plasma levels of plasma was with to in and by a Hepatic glucose production was as Z. Full Text PDF PubMed Scopus Google Scholar). is of activity of of body and is glucose the were with either or of as for of p38 Fasting and of we that p38 is activated by in and brown adipocytes and is necessary for transcription of the genes for the thermogenic uncoupling protein 1 (UCP1) and PGC-1α (13Cao W. Medvedev A.V. Daniel K.W. Collins S. J. Biol. Chem. 2001; 276: 27077-27082Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 16Cao W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar, 17Robidoux J. Cao W.H. Quan Q. Daniel K.W. Moukdar F. Bai B. Floering L.M. Collins S. Mol. Cell. Biol. 2005; 25: 5466-5479Crossref PubMed Scopus (92) Google we that p38 be activated in the liver by glucagon during fasting to control the expression of gluconeogenic this were with either or the p38 as described previously (13Cao W. Medvedev A.V. Daniel K.W. Collins S. J. Biol. Chem. 2001; 276: 27077-27082Abstract Full Text Full Text PDF PubMed Scopus (233) Google and to a of fed were As shown in phosphorylation of p38 was elevated by fasting and by As fasting reduced plasma glucose levels while with glucose levels in fed mice. As expression of the key gluconeogenic genes, and was in the liver by However, this was largely suppressed by with Together, these results a stimulatory role for p38 in hepatic of key gluconeogenic enzymes was by p38 inhibition in the were fasted for or fed with a of either or as described in of G6Pase and PGC-1α genes in the liver were by of RNA were as a and of and PGC-1α shown of with with the fed state or state with of p38 directly the role of p38 in was into through as under and in the or of As shown in was reduced by These results a role for p38 in gluconeogenesis in the of the p38α in of and Fasting the role of p38 in hepatic gluconeogenesis by we used siRNA against p38α by to the expression of the p38α p38α is the in hepatocytes K. S. B. J. J. N. M. Z. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar and not was in these As shown in of levels of p38 in the liver were reduced by siRNA the p38α gene was of PEPCK and PGC-1α genes were decreased by and and while plasma glucose levels were reduced by siRNA was in the range not that liver was not by adenoviral Together, these results a stimulatory role for p38 in expression of gluconeogenic genes in in Primary Hepatocytes the in the of gluconeogenesis by p38 directly in were from liver and with glucagon in the or of either or siRNA against As shown in of hepatocytes with adenoviral reduced p38 protein levels by in to The of and PGC-1α genes by glucagon was suppressed by either or siRNA Together, these results from primary hepatocytes a stimulatory role of p38 in expression of gluconeogenic genes, with observations from the in vivo p38 a in PGC-1α the role of p38 in transcription of the PGC-1α gene, a of hepatic gluconeogenesis (11Yoon 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. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1515) Google we the of p38 PGC-1α transcription in a cell The of the PGC-1α promoter a cAMP-response element (10Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. Spiegelman B. Montminy M. Nature. 2001; 413: 179-183Crossref PubMed Scopus (1134) Google Scholar, 16Cao W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar). As shown in the promoter was by glucagon suppressed by either the PKA inhibitor or by p38 or siRNA not PGC-1α by p38 in of the PEPCK of PGC-1α by p38 is for coactivator in transcription of genes W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar, P. Rhee J. J. Wu Z. Yoon J. C. S. B. Spiegelman B. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Rhee J. J. C. Puigserver P. J. S. H. P. Spiegelman B.M. 2004; PubMed Scopus Google Scholar). this phosphorylation is involved in transcription of the PEPCK gene in the PEPCK promoter was into and by glucagon with either the wild-type or a mutant of PGC-1α P. Rhee J. J. Wu Z. Yoon J. C. S. B. Spiegelman B. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). As shown in the PEPCK promoter was by glucagon, and of the wild-type PGC-1α this However, of the PGC-1α mutant suppressed glucagon of the These results are with the that phosphorylation of PGC-1α by p38 is of the events for transcription of the PEPCK of has been identified as important cAMP/PKA-dependent of gluconeogenic gene expression (10Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. Spiegelman B. Montminy M. Nature. 2001; 413: 179-183Crossref PubMed Scopus (1134) Google Scholar, 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. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1515) Google Scholar). p38 to be a downstream effector of PKA, as we have shown in studies in adipocytes (13Cao W. Medvedev A.V. Daniel K.W. Collins S. J. Biol. Chem. 2001; 276: 27077-27082Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 16Cao W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar, 17Robidoux J. Cao W.H. Quan Q. Daniel K.W. Moukdar F. Bai B. Floering L.M. Collins S. Mol. Cell. Biol. 2005; 25: 5466-5479Crossref PubMed Scopus (92) Google and this in hepatocytes. In p38 can CREB Q. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. M. A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). we that p38 be involved in activation of CREB in hepatocytes. this were either fed or fasted in the or of As shown in CREB phosphorylation was elevated by fasting in the liver and suppressed by blockade of that p38 is a component for CREB directly the role of p38 in activation of hepatocytes were by glucagon or in the or of or As shown in phosphorylation of both p38 and CREB was by glucagon or this was by inhibition of Together, these results the that CREB is downstream of p38 in the control of gluconeogenesis. CREB is a classic for PKA, our results that is a PKA for of p38 of Hepatic and in of the of diabetes in and in is elevation in hepatic and this is during fasting (see Refs. M. Res. 2001; PubMed Scopus Google Scholar and H. P. 2002; PubMed Scopus Google Scholar for review). we the role of p38 in expression of gluconeogenic genes under fasting in of type I diabetes by As shown in fasting decreased plasma glucose levels by were reduced to by blockade of p38 of p38 and expression of PEPCK and G6Pase genes in the liver were all elevated in fasted and by inhibition of p38 and Because of deficiency of insulin hepatic gluconeogenesis becomes unrestrained in diabetes, in In the of gluconeogenic is in diabetes, blood glucose We have identified p38 as a of the cAMP-dependent gluconeogenic by the expression of the PEPCK and G6Pase genes, as well as transcription that control been observations in the p38 activation in hepatocytes with and transcription of the PEPCK gene B. G. P. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar, J. J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C.H. Lee K. S. J. Diabetes. 2002; PubMed Scopus Google Scholar). However, the role of p38 in gluconeogenic genes as of the to fasting not been In of p38 in the liver, the transcriptional coactivator PGC-1α for the It is as important player in the from cAMP to gluconeogenesis (10Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. Spiegelman B. Montminy M. Nature. 2001; 413: 179-183Crossref PubMed Scopus (1134) Google Scholar, 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. Spiegelman B.M. Nature. 2001; 413: 131-138Crossref PubMed Scopus (1515) Google and we in brown adipocytes that both phosphorylation and transcription of PGC-1α are of p38 W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google Scholar). In hepatocytes we as in p38 activity was activated downstream of PKA in expression of the PGC-1α It is these that of PGC-1α gene transcription by p38 be in cell the specific transcription of p38 between in adipocytes the cAMP-dependent activation of p38 to phosphorylation of which the in the PGC-1α gene to transcription W. Daniel K.W. Robidoux J. Puigserver P. Medvedev A.V. Bai X. Floering L.M. Spiegelman B.M. Collins S. Mol. Cell. Biol. 2004; 24: 3057-3067Crossref PubMed Scopus (439) Google in the liver the is studies in hepatocytes have shown that be involved in the control of PEPCK promoter activity in cell J. J.D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C.H. Lee K. S. J. Diabetes. 2002; PubMed Scopus Google Scholar). we of activation in the liver during fasting not and Herzig (10Herzig S. Long F. Jhala U.S. Hedrick S. Quinn R. Bauer A. Rudolph D. Schutz G. Yoon C. Puigserver P. Spiegelman B. Montminy M. Nature. 2001; 413: 179-183Crossref PubMed Scopus (1134) Google previously that CREB was for expression of PGC-1α and gluconeogenic genes in the Although the role for was not directly in that study, is very that of a of CREB have inhibited S. M. S. D. C. Mol. Cell. Biol. PubMed Scopus Google Scholar). In our phosphorylation of CREB in the liver and hepatocytes was elevated by fasting and by inhibition of It is this specific to CREB phosphorylation from p38 and p38 is for CREB activation in this tissue CREB is a classic for In we have that p38 plays a stimulatory role in hepatic gluconeogenesis. The of p38 is glucagon, which is elevated in the blood during fasting and in diabetes. However, and such as can be of p38 T. Med. Chem. 1999; Google Scholar, J. P. E. A. E. Biol. 2001; PubMed Scopus Google Scholar, Diabetes. 2003; PubMed Scopus Google Scholar, H. S. R.N. J. Pharmacol. Exp. 2003; PubMed Scopus Google are all to be elevated in the of fasting in diabetes G. PubMed Scopus Google Scholar, J.C. D. PubMed Scopus Google Scholar, J. 2003; PubMed Scopus Google Scholar, A. de G. A. J. Physiol. 2003; PubMed Scopus Google Scholar, 2004; PubMed Scopus Google Scholar). A understanding of the signaling that can p38 in the liver new into the unrestrained gluconeogenesis in diabetes. In addition to the stimulatory role in gluconeogenesis described p38 is for role in a of (see Ref. J. J. A. Biochem. 2003; PubMed Scopus Google Scholar for review). diabetes is as Chen G. R. Newgard C.B. J. 2003; PubMed Scopus Google Scholar, M. Med. 2004; PubMed Scopus Google Scholar, J. Clin. Investig. 2005; PubMed Scopus Google Scholar, E. Diabetes. 2005; 54: PubMed Scopus Google Scholar). Although that inhibition of p38 be for the of diabetes, by this in we be in a to identify other for We Dr. Bruce Spiegelman for the PGC-1α We and for for of hepatic glucose production and Dr. for and We Dr. Jianhua for the PEPCK promoter
Cao et al. (Sat,) studied this question.
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