GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene

GIP (glucose-dependent insulinotropic polypeptide) is a gastrointestinal hormone that regulates pancreatic islet function. Additionally, emerging evidence suggests an important physiological role for GIP in the regulation of adipocyte metabolism. In previous studies on the lipogenic effects of GIP, it was shown to increase adipocyte lipoprotein lipase (LPL) activity in both differentiated 3T3-L1 cells and human adipocytes through a pathway involving activation of protein kinase B (PKB)/Akt. In the current study, we examined the effects of GIP on LPL gene expression. GIP in the presence of insulin increased LPL gene expression in human adipocytes and LPL promoter activity in GIP receptor-expressing HEK-293 cells, and both effects were greatly reduced by the transcription inhibitor actinomycin D. Subsequent studies established that GIP increased phosphorylation of Serine 133 in cAMP-response element binding protein (CREB) and the nuclear localization of cAMP-responsive CREB coactivator 2 (TORC2) through a pathway involving phosphatidylinositol 3-kinase (PI3-K), PKB, and AMP-activated protein kinase (AMPK). However, in the presence of insulin, GIP failed to activate the cAMP/PKA pathway. Knockdown of CREB and TORC2 using RNA interference reduced LPL expression, supporting a functional regulatory role. GIP-induced phospho-CREB and TORC2 were shown to bind to a cAMP-response element (-II) site in the human LPL promoter and GIP increased protein-protein interactions of these two factors. The lipogenic effects of GIP in the presence of insulin are therefore at least partially mediated by upregulation of adipocyte LPL gene transcription through a pathway involving PI3-K/PKB/AMPK-dependent CREB/TORC2 activation. GIP (glucose-dependent insulinotropic polypeptide) is a gastrointestinal hormone that regulates pancreatic islet function. Additionally, emerging evidence suggests an important physiological role for GIP in the regulation of adipocyte metabolism. In previous studies on the lipogenic effects of GIP, it was shown to increase adipocyte lipoprotein lipase (LPL) activity in both differentiated 3T3-L1 cells and human adipocytes through a pathway involving activation of protein kinase B (PKB)/Akt. In the current study, we examined the effects of GIP on LPL gene expression. GIP in the presence of insulin increased LPL gene expression in human adipocytes and LPL promoter activity in GIP receptor-expressing HEK-293 cells, and both effects were greatly reduced by the transcription inhibitor actinomycin D. Subsequent studies established that GIP increased phosphorylation of Serine 133 in cAMP-response element binding protein (CREB) and the nuclear localization of cAMP-responsive CREB coactivator 2 (TORC2) through a pathway involving phosphatidylinositol 3-kinase (PI3-K), PKB, and AMP-activated protein kinase (AMPK). However, in the presence of insulin, GIP failed to activate the cAMP/PKA pathway. Knockdown of CREB and TORC2 using RNA interference reduced LPL expression, supporting a functional regulatory role. GIP-induced phospho-CREB and TORC2 were shown to bind to a cAMP-response element (-II) site in the human LPL promoter and GIP increased protein-protein interactions of these two factors. The lipogenic effects of GIP in the presence of insulin are therefore at least partially mediated by upregulation of adipocyte LPL gene transcription through a pathway involving PI3-K/PKB/AMPK-dependent CREB/TORC2 activation. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) constitute the hormonal arm of the enteroinsular axis that conveys insulinotropic signals from the gut to pancreatic β-cells during a meal. It has been estimated that the combined effects of these incretin hormones contribute >60% of the total insulin secreted. Analogs of GIP (1Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (3101) Google Scholar, 2McIntosh C.H.S. Widenmaier S. Kim S.J. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).Vitam. Horm. 2009; 80: 409-471Crossref PubMed Scopus (144) Google Scholar) and GLP-1 (3Davidson M.B. Bate G. Kirkpatrick P. Exenatide.Nat. Rev. Drug Discov. 2005; 4: 713-714Crossref PubMed Scopus (85) Google Scholar) have been shown to improve glucose homeostasis in animal models of diabetes and the long-acting incretin analogs (mimetics) exendin-4 (Exenatide) and liraglutide (1Drucker D.J. Nauck M.A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.Lancet. 2006; 368: 1696-1705Abstract Full Text Full Text PDF PubMed Scopus (3101) Google Scholar, 3Davidson M.B. Bate G. Kirkpatrick P. Exenatide.Nat. Rev. Drug Discov. 2005; 4: 713-714Crossref PubMed Scopus (85) Google Scholar, 4Harder H. Nielsen L. Tu D.T.T. Astrup A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes.Diabetes Care. 2004; 27: 1915-1921Crossref PubMed Scopus (185) Google Scholar, 5DeFronzo R.A. Ratner R.E. Han J. Kim D.D. Fineman M.S. Baron A.D. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.Diabetes Care. 2005; 28: 1092-1100Crossref PubMed Scopus (1346) Google Scholar), as well as highly selective inhibitors of the incretin-degrading enzyme dipeptidyl peptidase-IV (6Deacon C.F. Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for type 2 diabetes.Expert Opin. Investig. Drugs. 2007; 16: 533-545Crossref PubMed Scopus (50) Google Scholar, 7Rosenstock J. Baron M.A. Dejager S. Mills D. Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial.Diabetes Care. 2007; 30: 217-223Crossref PubMed Scopus (258) Google Scholar, 8McIntosh C.H.S. Dipeptidyl peptidase IV inhibitors and diabetes therapy.Front. Biosci. 2008; 13: 1753-1773Crossref PubMed Scopus (53) Google Scholar), have been recently introduced as therapeutics. Because both GIP and GLP-1 also influence β-cell mass (2McIntosh C.H.S. Widenmaier S. Kim S.J. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).Vitam. Horm. 2009; 80: 409-471Crossref PubMed Scopus (144) Google Scholar, 9Brubaker P.L. Drucker D.J. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system.Endocrinology. 2004; 145: 2653-2659Crossref PubMed Scopus (478) Google Scholar, 10Drucker D.J. The role of gut hormones in glucose homeostasis.J. Clin. Invest. 2007; 117: 24-32Crossref PubMed Scopus (492) Google Scholar, 11Yusta B. Baggio L.L. Estall J.L. Koehler J.A. Holland D.P. Li H. Pipeleers D. Ling Z. Drucker D.J. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress.Cell Metab. 2006; 4: 391-406Abstract Full Text Full Text PDF PubMed Scopus (334) Google Scholar, 12Ehses J.A. Casilla V.R. Doty T. Pospisilik J.A. Winter K.D. Demuth H.U. Pederson R.A. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase.Endocrinology. 2003; 144: 4433-4445Crossref PubMed Scopus (151) Google Scholar, 13Kim S.J. Winter K. Nian C. Tsuneoka M. Koda Y. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and down-regulation of bax expression.J. Biol. Chem. 2005; 280: 22297-22307Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 14Kim S.J. Nian C. Widenmaier S. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide mediated up-regulation of β-cell anti-apoptotic Bcl-2 gene expression is coordinated by cAMP-response element binding protein (CREB) and cAMP-responsive CREB coactivator 2.Mol. Cell. Biol. 2008; 28: 1644-1656Crossref PubMed Scopus (112) Google Scholar, 15Widenmaier S.B. Ao Z. Kim S.J. Warnock G. McIntosh C.H.S. Suppression of p38 MAPK and JNK via Akt-mediated inhibition of apoptosis signal regulating kinase 1 constitutes a core component of the beta-cell pro-survival effects of glucose-dependent insulinotropic polypeptide.J. Biol. Chem. 2009; 284: 30372-30382Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar), as well as various gastrointestinal and adipose tissue functions (2McIntosh C.H.S. Widenmaier S. Kim S.J. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).Vitam. Horm. 2009; 80: 409-471Crossref PubMed Scopus (144) Google Scholar, 10Drucker D.J. The role of gut hormones in glucose homeostasis.J. Clin. Invest. 2007; 117: 24-32Crossref PubMed Scopus (492) Google Scholar), incretin-based drugs may demonstrate additional effects. Although there has been great progress in understanding the mechanisms involved in regulating adipocyte metabolism (16Spiegelman B.M. Flier J.S. Obesity and the regulation of energy balance.Cell. 2001; 104: 531-543Abstract Full Text Full Text PDF PubMed Scopus (1958) Google Scholar, 17MacDougald O.A. Mandrup S. Adipogenesis: forces that tip the scales.Trends Metab. 13: Full Text Full Text PDF PubMed Scopus Google Scholar, A.D. metabolism and 2009; Full Text Full Text PDF PubMed Scopus Google Scholar), the of gastrointestinal hormones have been GIP is in to R.A. and insulinotropic in the PubMed Google Scholar, T. Rev. PubMed Scopus Google Scholar) and there is evidence supporting a role for GIP in in GIP in T. K. K. B. of polypeptide on of in Clin. Invest. PubMed Scopus Google Scholar) and to in Nauck M. of polypeptide (GIP) on in Metab. PubMed Scopus Google Scholar), of GIP in following a Nauck M. of polypeptide (GIP) on in Metab. PubMed Scopus Google In of effect of polypeptide on the of in PubMed Scopus Google Scholar) A. T. J. of polypeptide (GIP) on the of in PubMed Scopus Google Scholar) GIP the of that is Because GIP insulin during a and insulin is a hormonal of of the of GIP on metabolism in is mediated via β-cell However, a of studies have shown that GIP adipocyte (2McIntosh C.H.S. Widenmaier S. Kim S.J. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).Vitam. Horm. 2009; 80: 409-471Crossref PubMed Scopus (144) Google Scholar, C.H.S. Nian C. G. S. Pederson R.A. Glucose-dependent insulinotropic polypeptide stimulation of in differentiated inhibition by PubMed Scopus Google Scholar, GIP and PubMed Google Scholar, S.J. Nian C. McIntosh C.H.S. of lipoprotein lipase by dependent insulinotropic polypeptide in role for a protein kinase and AMP-activated protein kinase Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, S.J. Nian C. McIntosh C.H.S. is a of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), of lipoprotein lipase (LPL) activity S.J. Nian C. McIntosh C.H.S. of lipoprotein lipase by dependent insulinotropic polypeptide in role for a protein kinase and AMP-activated protein kinase Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, S.J. Nian C. McIntosh C.H.S. is a of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar, polypeptide lipoprotein lipase activity in 28: PubMed Scopus Google Scholar, the of glucose-dependent insulinotropic polypeptide and glucagon-like on lipoprotein lipase activity in of adipose Google It was that GIP in the presence of insulin increased the of LPL enzyme activity and in differentiated 3T3-L1 adipocytes and human adipocytes through a pathway involving increased phosphorylation of protein kinase B (PKB) and and AMP-activated protein kinase phosphorylation S.J. Nian C. McIntosh C.H.S. of lipoprotein lipase by dependent insulinotropic polypeptide in role for a protein kinase and AMP-activated protein kinase Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google However, it was as to in LPL activity from GIP-induced in In the current study, we that GIP human adipocyte LPL gene transcription and that phosphorylation of cAMP-response element binding protein (CREB) and nuclear localization of TORC2 are involved in of the LPL human adipocytes from were from body mass and for of the adipose tissue were from the patients by lipoprotein lipase activity was to enzyme activity to the activity is as activity to protein RNA was from adipocytes and were by of were in the to LPL expression, were in the control The and for the of LPL were as the and was as a of were from cells as by P. of binding with from a of PubMed Scopus Google cells were with and with 1 1 and were and the were in B 1 1 and and on for of the by the were and to and were as nuclear and to of the were on a and of the was with phospho-CREB and LPL Because were and TORC2 was were by using of adipocytes was using phospho-CREB and TORC2 and with and were with and using a were using the GIP receptor HEK-293 cells S.J. Han J.S. Warnock G. D. McIntosh C.H.S. for the of a by glucose-dependent insulinotropic protein kinase Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar) were with 1 of human LPL to of LPL and 1 of control the CREB expression and CREB were by C. of and M. were using for 4 to the the following cells were with GIP for the in the with and in were using the and activity is as the activity of the effect of of CREB and TORC2 on LPL expression, human adipocytes were with a of for CREB TORC2 and that in to of the as cells were and for The of in CREB and TORC2 protein expression was by using phospho-CREB and adipocytes were for 30 with GIP GLP-1 in the presence of insulin and in the cell were using the cell were with using protein as in The were by and with cells were to and TORC2 were from using protein and was and by using the cAMP-response element site of the human LPL are as with the of in the was using with as in the In with S.J. Nian C. 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Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), of human adipocytes with GIP in the presence of insulin in in LPL activity with there were effects of GLP-1 LPL activation in human adipocytes was by in protein and shown in and GIP in the presence of insulin GLP-1 increased LPL as well as protein expression. well with LPL activity Because in LPL to in gene transcription we LPL activity in the presence of the transcription actinomycin D. shown in and in both LPL activity and protein expression in to GIP were greatly reduced by actinomycin D. that GIP was of LPL gene expression, cells were with a human LPL promoter and for with insulin GIP GLP-1 GIP and GLP-1 increased promoter activity these that in LPL activity were at least partially to activation of the LPL CREB a role in of the LPL was on the that CREB activation been as an of LPL expression in cell J. B. S. J. lipase expression in cells is by and protein kinase PubMed Scopus Google Scholar, B. G. M. C. J. M. S. J. and regulation of the lipoprotein lipase gene in human Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), a in been in the LPL promoter M. and Full Text Full Text PDF PubMed Scopus Google Additionally, we shown that in was to nuclear of TORC2 and CREB activation in β-cells S.J. Nian C. Widenmaier S. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide mediated up-regulation of β-cell anti-apoptotic Bcl-2 gene expression is coordinated by cAMP-response element binding protein (CREB) and cAMP-responsive CREB coactivator 2.Mol. Cell. Biol. 2008; 28: 1644-1656Crossref PubMed Scopus (112) Google adipocytes were therefore with GIP GLP-1 and were on nuclear using phospho-CREB shown in GIP GLP-1 increased the of CREB and the nuclear localization of TORC2 and the of and of adipocytes in an that GIP increased both nuclear of phospho-CREB and TORC2 nuclear that CREB phosphorylation a role in GIP-induced of were using various CREB with the LPL promoter in is an of CREB that with binding to the C. M. A. M. of human on Cell. Biol. PubMed Scopus Google a CREB on of the CREB binding gene transcription by phosphorylation of CREB at Full Text PDF PubMed Scopus Google is a a CREB as a in K. H. M. of a CREB with activity in Cell. Biol. PubMed Scopus Google gene expression via the of and C. M. A. M. of human on Cell. Biol. PubMed Scopus Google were of LPL promoter activity and GIP of the LPL promoter was greatly with control the was and LPL promoter activity was increased and activation of the LPL promoter was with control was also increased a role for CREB in of the LPL functional of CREB and TORC2 in the regulation of LPL expression in human RNA interference was shown in and RNA interference in in of phospho-CREB and TORC2 with reduced LPL protein expression. CREB and TORC2 in in LPL that as of LPL expression. Because GIP-induced in adipocyte were shown to with increased phosphorylation of S.J. Nian C. McIntosh C.H.S. of lipoprotein lipase by dependent insulinotropic polypeptide in role for a protein kinase and AMP-activated protein kinase Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar), was to the of with of the two selective the effects of GIP on the phosphorylation of and nuclear localization of TORC2 In a study, with the in of TORC2 in the with the in of TORC2 from the Additionally, inhibitor was shown to increase LPL activity the activity regulates CREB/TORC2 through a pathway involving adipocytes were in and for with GIP in the presence of insulin of inhibition on in and nuclear CREB/TORC2 adipocytes were for with insulin GIP in the presence of of on CREB/TORC2 adipocytes were for with insulin GIP in the presence of inhibitor inhibitor was to cells during 1 as well as GIP were from and were TORC2 and are from nuclear and and are from of on LPL adipocytes were as and LPL activity was as in and of GIP GLP-1 on adipocytes were as and with GIP GLP-1 in the presence of insulin and in the cell of inhibition on in and nuclear CREB/TORC2 adipocytes were as and insulin GIP, GLP-1 in the presence of was to cells during 1 as well as during GIP were from and were with and of inhibition on CREB/TORC2 adipocytes were for with insulin GIP in the presence of inhibitor were from and were with and are of in was using with we that insulin the of GIP to activate C.H.S. Nian C. G. S. Pederson R.A. Glucose-dependent insulinotropic polypeptide stimulation of in differentiated inhibition by PubMed Scopus Google Scholar) and in the current were in the presence of However, been to involved in of TORC2 to the and phosphorylation of nuclear CREB in β-cells S.J. Nian C. Widenmaier S. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide mediated up-regulation of β-cell anti-apoptotic Bcl-2 gene expression is coordinated by cAMP-response element binding protein (CREB) and cAMP-responsive CREB coactivator 2.Mol. Cell. Biol. 2008; 28: 1644-1656Crossref PubMed Scopus (112) Google It was therefore important to the effect of GIP on the cAMP/PKA pathway in human of human adipocytes with a of in increase in with control with GIP GLP-1 in the presence of insulin effects on Additionally, the effects of GIP on and CREB/TORC2 were by the inhibitors and that GIP in the presence of insulin activity of CREB/TORC2 via activation of the pathway However, inhibition of with the selective inhibitor IV the effects of GIP on the phosphorylation of CREB and nuclear localization of TORC2 In a study, inhibitors and the effects of GIP on LPL and protein expression. In an inhibitor was shown to the effect of GIP on LPL expression. inhibitors effects these that and are of the activation pathway in human adipocytes cAMP/PKA a role. shown in protein-protein phospho-CREB and TORC2 in nuclear from of phospho-CREB and TORC2 was also using Because the to the CREB G. L. M. of CREB Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. of cAMP-responsive J. 2007; PubMed Scopus Google Scholar) these increased the transcription factor and coactivator in the protein-protein and of phospho-CREB and TORC2 were by with inhibitors activation to functional in the LPL we the of in gene and were on to regulation in to in gene expression during and to the of the human LPL promoter to of LPL using the the presence of two that we have and and have and to the the functional for binding to the human LPL promoter was by of using shown in and GIP GLP-1 increased both phospho-CREB and TORC2 binding to of the LPL that is the functional element of the human LPL promoter involved in to The of studies on GIP have on incretin with effects on the pancreatic is the role of GIP in adipose tissue metabolism. GIP has been shown to from in adipose tissue J. L. J. of the polypeptide and glucagon-like on in of adipose PubMed Scopus Google Scholar), as well as adipose tissue B. effects of polypeptide at physiological of effects on and glucose in adipose PubMed Scopus Google In previous it was shown that GIP increased LPL activity and in both 3T3-L1 cells and human adipocytes through a pathway involving increased phosphorylation of and in and phosphorylation S.J. Nian C. McIntosh C.H.S. of lipoprotein lipase by dependent insulinotropic polypeptide in role for a protein kinase and AMP-activated protein kinase Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google The regulation of adipocyte LPL expression and is involving and M. and Full Text Full Text PDF PubMed Scopus Google Scholar, H. from gene to J. Metab. 2009; PubMed Scopus Google The current was therefore in to the mechanisms involved in in LPL activity in human is an important of the that effects in tissue are involved in the of with the of (2McIntosh C.H.S. Widenmaier S. Kim S.J. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).Vitam. Horm. 2009; 80: 409-471Crossref PubMed Scopus (144) Google Scholar) and the for GIP and GIP analogs as in 2 GIP was to increase LPL promoter activity and in the presence of insulin both LPL and protein were increased in human adipocytes of the LPL gene was shown to a to in LPL activity were greatly reduced by the transcription inhibitor actinomycin However, additional effects of GIP on activation and of of enzyme may also In the effect on LPL gene expression. for the of CREB in the regulation of LPL expression has been in studies on cells B. G. M. C. J. M. S. J. and regulation of the lipoprotein lipase gene in human Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and the M. and Full Text Full Text PDF PubMed Scopus Google of in CREB is important for the of and and with TORC2 in increased GIP of human adipocytes was to increase of CREB and nuclear localization of TORC2 functional of CREB and TORC2 in the regulation of LPL expression was by RNA interference of phospho-CREB and TORC2 was in studies and evidence for protein-protein CREB and TORC2 in nuclear from cells of human LPL promoter the presence of two and to have been as a in in the of the human LPL promoter M. and Full Text Full Text PDF PubMed Scopus Google Scholar, H. from gene to J. Metab. 2009; PubMed Scopus Google Scholar, C. J. S. K. D. C. L. A. of the human lipoprotein lipase gene and of the lipase gene PubMed Scopus (185) Google Scholar), the been The human and and with the was to as the functional for GIP is therefore evidence for a pathway in human adipocytes involving LPL gene expression. and at a site to the human with the and to the human and L. J. C. D. L. A. and of of the promoter for the lipoprotein lipase Comparison with the and human PubMed Scopus Google It is therefore that the is as The pathway that mediated GIP in the human adipocyte is to that shown to involved in activation of gene expression in β-cells S.J. Nian C. Widenmaier S. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide mediated up-regulation of β-cell anti-apoptotic Bcl-2 gene expression is coordinated by cAMP-response element binding protein (CREB) and cAMP-responsive CREB coactivator 2.Mol. Cell. Biol. 2008; 28: 1644-1656Crossref PubMed Scopus (112) Google However, was to a component of the activation pathway for TORC2 in β-cells S.J. Nian C. Widenmaier S. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide mediated up-regulation of β-cell anti-apoptotic Bcl-2 gene expression is coordinated by cAMP-response element binding protein (CREB) and cAMP-responsive CREB coactivator 2.Mol. Cell. Biol. 2008; 28: 1644-1656Crossref PubMed Scopus (112) Google Scholar), a pathway is a central in the regulation of LPL gene expression in the human adipocyte also CREB K. M. CREB is a regulatory for the protein kinase Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. K. activation of CREB by and 2007; PubMed Scopus Google Scholar), and the selective inhibitor IV the effects of GIP on LPL and protein expression as well as CREB phosphorylation It is therefore that a via TORC2 and phosphorylation of CREB of has also been shown to involved in GIP-induced of adipocyte glucose L. J. Glucose-dependent insulinotropic polypeptide adipocyte and glucose in through 2007; Full Text Full Text PDF PubMed Scopus Google However, activation of is important in regulation of in the of insulin increased have been in and differentiated 3T3-L1 cells to GIP C.H.S. Nian C. G. S. Pederson R.A. Glucose-dependent insulinotropic polypeptide stimulation of in differentiated inhibition by PubMed Scopus Google Scholar, GIP are on PubMed Scopus Google Scholar, effects of Inhibitory Horm. 16: Google Although the of a of GIP is as (2McIntosh C.H.S. Widenmaier S. Kim S.J. Glucose-dependent insulinotropic polypeptide (Gastric Inhibitory Polypeptide; GIP).Vitam. Horm. 2009; 80: 409-471Crossref PubMed Scopus (144) Google Scholar, C.H.S. Nian C. G. S. Pederson R.A. Glucose-dependent insulinotropic polypeptide stimulation of in differentiated inhibition by PubMed Scopus Google Scholar), insulin are GIP may important for β-cells for glucose stimulation by at GIP insulin insulin in inhibition of the two hormones to in the current is the of human to GIP-induced It was that the effects of GIP on the pathway in 3T3-L1 adipocytes S.J. Nian C. McIntosh C.H.S. is a of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google of in effects of GIP on that is a of LPL activation in the S.J. Nian C. McIntosh C.H.S. is a of glucose-dependent insulinotropic polypeptide (GIP) stimulation of lipoprotein lipase (LPL) activity in Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google is in and adipocytes S. Opin. 2006; PubMed Scopus Google Scholar, J. S. K. gene expression in human adipocytes is to insulin PubMed Scopus Google Scholar), in with the of protein in adipose tissue A. S. in to and in 2001; PubMed Scopus Google Because the in the LPL promoter with the it is that it is with the pathway for regulating LPL gene expression in the In GIP in the presence of insulin increased LPL gene expression in human LPL promoter studies and it was established that GIP increased nuclear of TORC2 and binding to phospho-CREB at a site in the human LPL effects a PI3-K/PKB/AMPK-dependent pathway. Although is the in of GIP on human adipose tissue the current evidence supporting a role in physiological effect is in of and to the of is The C. of and M. for and CREB AMP-activated protein kinase cAMP-response element cAMP-response element binding protein glucose-dependent insulinotropic polypeptide GIP receptor glucagon-like peptide-1 phosphatidylinositol 3-kinase protein kinase B cAMP-responsive CREB coactivator 2

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