Adipocyte expression of the glucose-dependent insulinotropic polypeptide receptor involves gene regulation by PPARγ and histone acetylation

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that exerts insulinotropic and growth and survival effects on pancreatic β-cells. Additionally, there is increasing evidence supporting an important role for GIP in the regulation of adipocyte metabolism. In the current study we examined the molecular mechanisms involved in the regulation of GIP receptor (GIPR) expression in 3T3-L1 cells. GIP acted synergistically with insulin to increase neutral lipid accumulation during progression of 3T3-L1 preadipocytes to the adipocyte phenotype. Both GIPR protein and mRNA expression increased during 3T3-L1 cell differentiation, and this increase was associated with upregulation of nuclear levels of sterol response element binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor γ (PPARγ), as well as acetylation of histones H3/H4. The PPARγ receptor agonists LY171883 and rosiglitazone increased GIPR expression in differentiated 3T3-L1 adipocytes, whereas the antagonist GW9662 ablated expression. Additionally, both PPARγ and acetylated histones H3/H4 were shown to bind to a region of the GIPR promoter containing the peroxisome proliferator response element (PPRE). Knockdown of PPARγ in differentiated 3T3-L1 adipocytes, using RNA interference, reduced GIPR expression, supporting a functional regulatory role. Taken together, these studies show that GIP and insulin act in a synergistic manner on 3T3-L1 cell development and that adipocyte GIPR expression is upregulated through a mechanism involving interactions between PPARγ and a GIPR promoter region containing an acetylated histone region. Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that exerts insulinotropic and growth and survival effects on pancreatic β-cells. Additionally, there is increasing evidence supporting an important role for GIP in the regulation of adipocyte metabolism. In the current study we examined the molecular mechanisms involved in the regulation of GIP receptor (GIPR) expression in 3T3-L1 cells. GIP acted synergistically with insulin to increase neutral lipid accumulation during progression of 3T3-L1 preadipocytes to the adipocyte phenotype. Both GIPR protein and mRNA expression increased during 3T3-L1 cell differentiation, and this increase was associated with upregulation of nuclear levels of sterol response element binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor γ (PPARγ), as well as acetylation of histones H3/H4. The PPARγ receptor agonists LY171883 and rosiglitazone increased GIPR expression in differentiated 3T3-L1 adipocytes, whereas the antagonist GW9662 ablated expression. Additionally, both PPARγ and acetylated histones H3/H4 were shown to bind to a region of the GIPR promoter containing the peroxisome proliferator response element (PPRE). Knockdown of PPARγ in differentiated 3T3-L1 adipocytes, using RNA interference, reduced GIPR expression, supporting a functional regulatory role. Taken together, these studies show that GIP and insulin act in a synergistic manner on 3T3-L1 cell development and that adipocyte GIPR expression is upregulated through a mechanism involving interactions between PPARγ and a GIPR promoter region containing an acetylated histone region. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two major incretin hormones that potentiate glucose-stimulated insulin secretion during a meal and exert additional beneficial effects on β-cell proliferation and survival (1Brubaker P.L. Drucker D.J. 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M. expression of glucose-dependent insulinotropic polypeptide is to in a adipocyte J. 2008; PubMed Scopus Google Scholar), and mechanisms its induction have not been additional of the current was to involved in the regulation of adipocyte GIPR expression. progression of 3T3-L1 preadipocytes to the adipocyte GIP was to act synergistically with insulin to increase neutral lipid In studies of both and differentiated 3T3-L1 GIPR expression was shown to increased by a mechanism involving peroxisome proliferator-activated receptor γ activation and acetylation of histones the nuclear PPARγ to a peroxisome proliferator response element in a region of the GIPR promoter that acetylated histones H3/H4. to the of involved in the regulation of adipocyte GIPR expression. 3T3-L1 were in containing glucose and with were were for or with with in the or of and GIP with or insulin as shown in of the adipocyte was by or In studies of differentiated 3T3-L1 adipocytes, was for with a differentiation, adipocytes were with a PPARγ agonist or antagonist as in the were and for 2 by in a of The by J.L. of and by with PubMed Scopus Google Scholar) was to the of was to the was by and the was with a 3T3-L1 preadipocytes were for as in the to and with and The lipid neutral and a of M. is highly to as by lipid in of 2009; PubMed Scopus Google Scholar). were by a were as by P. of binding with a number of PubMed Scopus Google Scholar). were with and of A 1 1 and were and the resulting were in of B 1 1 and and on for the was by the were and to and were as nuclear and to of between the and nuclear 3T3-L1 preadipocytes or adipocytes were on a and of the was with and and and and histone and GIPR and and were were by using RNA was adipocytes, and were by was in to GIPR expression, whereas of was in the control The and for the of GIPR were and is and is The and for the of were and the and was as the of were to and PPARγ were using protein A or or was as control, and of the of in the was as control, for of the region were and to The for the control were and to cell nuclear were and with or using protein A The were by and with PPARγ 3T3-L1 adipocytes were with a of for PPARγ using and for The in PPARγ expression was by using are as of the and the number of is in the was using with a or a as in The effects of of GIP and insulin on were in 3T3-L1 for in the or of and as shown in of neutral during development of the adipocyte was by and were for differentiation, for its with GIP not increase neutral lipid accumulation whereas insulin increased lipid levels and 1 insulin effect on neutral lipid accumulation the of GIP accumulation GIP of or lipid accumulation in a A of GIP insulin levels of lipid accumulation to with the of insulin for 3T3-L1 cell of lipid by using to that using with a increase in the of increasing of insulin GIP Taken together, these demonstrated that insulin 3T3-L1 cell differentiation, GIP acted synergistically to potentiate examined GIPR expression during the of adipogenesis in response to the with GIP and with 1 insulin and GIPR mRNA was with a GIP and 1 a increase in GIPR mRNA levels was 4 and insulin levels to in the of or GIP an of expression GIPR protein expression was in containing a of insulin to the of protein GIPR mRNA levels the of adipocyte demonstrated with neutral lipid and study molecular mechanisms involved in the upregulation of GIPR mRNA during of 3T3-L1 we on transcription to upregulated during that have been shown to central in the regulation of cell development are adipocyte factor response element binding protein 1c and the nuclear receptor A functional was recently in the rat GIPR gene D. M. N. J.L. and of GIP receptor expression in by PPARγ mechanism for the GIP in 2 2010; PubMed Scopus Google Scholar), and both Pospisilik J.A. J.A. N. McIntosh C.H.S. Pederson R.A. A for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta J. 2003; PubMed Scopus Google Scholar, N. McIntosh C.H.S. Kieffer T.J. Pederson R.A. glucose-dependent insulinotropic polypeptide receptor expression in PubMed Scopus Google Scholar) and PPARγ D. M. N. J.L. and of GIP receptor expression in by PPARγ mechanism for the GIP in 2 2010; PubMed Scopus Google Scholar) have been in the regulation of GIPR mRNA expression in pancreatic β-cells. 3T3-L1 preadipocytes were as in the to and of nuclear were using or was in 3T3-L1 levels not during or with increasing peptide In nuclear of both and were upregulated during adipocyte of insulin were of increasing expression the synergistic of GIP and PPARγ expression and acetylation of histones H3/H4 increase during 3T3-L1 adipocyte The of expression of and PPARγ and acetylation of histones H3/H4 during 3T3-L1 adipocyte is 3T3-L1 preadipocytes were as in the to nuclear were and were using and histone of are are shown for PPARγ and were and with the control, histone are control with 1 for 1 was using with control with 1 for 1 the The of histone that regulate gene transcription by of transcription to target and the in nuclear of both and in the current study to were associated with 3T3-L1 preadipocytes were as in the to and were with nuclear using H3/H4. As shown in acetylation of histone and histone increased during with GIP insulin or with insulin that histone were involved in the regulation of adipocyte GIPR gene In of the of in during 3T3-L1 cell adipogenesis and the strong evidence for in the regulation of β-cell GIPR expression D. M. N. J.L. and of GIP receptor expression in by PPARγ mechanism for the GIP in 2 2010; PubMed Scopus Google Scholar), we on its in regulating adipocyte GIPR expression. The functional of PPARγ in the regulation of adipocyte GIPR expression was examined using PPARγ agonists and an 3T3-L1 preadipocytes were for in 1 insulin or as shown in in the or of the PPARγ agonist LY171883 to expression of GIPR protein and mRNA as well as accumulation of PPARγ in the LY171883 accumulation of lipid it not nuclear expression levels In with an study A. M.A. proliferator and signaling and Sci. A. PubMed Scopus Google Scholar), LY171883 adipocyte in the of and insulin differentiated 3T3-L1 were for with a PPARγ and this in increases in nuclear as well as GIPR mRNA levels and protein expression with the PPARγ GW9662 to a of nuclear and GIPR protein and mRNA levels In mRNA levels were reduced by to in control Taken together, these that adipocyte GIPR expression in 3T3-L1 is through a involving increased nuclear of activation increases 3T3-L1 GIPR expression in differentiated 3T3-L1 preadipocytes were for with differentiation, adipocytes were with the of rosiglitazone for in the or of the GW9662 Effects of PPARγ agonist and antagonist on nuclear PPARγ expression are were and were using PPARγ and histone Effects of PPARγ agonist and antagonist on adipocyte GIPR protein expression are 3T3-L1 adipocytes were as and were using GIPR and Effects of PPARγ agonist and antagonist on adipocyte GIPR mRNA expression are 3T3-L1 adipocytes were as and was to GIPR mRNA shown as the control to expression in and are of was using with control with rosiglitazone and the of PPARγ in of the adipocyte the of PPARγ binding to the in the promoter was by using with insulin GIP or insulin increased the of both PPARγ and acetylated histones H3/H4 with the GIPR region in the and these were by with the PPARγ agonist LY171883 to the of nuclear PPARγ its with the GIPR was following GW9662 studies demonstrated protein interactions between PPARγ and histone acetylated or histone acetylated the of PPARγ and acetylated histones H3/H4 in of the adipocyte the functional of PPARγ in of the adipocyte RNA was As shown in in in protein expression, associated with reduced GIPR mRNA PPARγ is to a of adipocyte GIPR expression. GIP an role in the regulation of β-cell function C.H.S. Widenmaier S. Kim S.J. Glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide; GIP).Vitam. Horm. 2009; 80: 409-471Crossref PubMed Scopus (142) Google Scholar), its role in regulating the adipocyte recently been In the current we on two GIP potentiate of 3T3-L1 a cell of and are involved in the regulation of adipocyte GIPR is a with growth the cell and been to a role in the of C. growth is an of the of Biol. Chem. Full Text PDF PubMed Google Scholar, M. A. M. a involved in in J. Biol. 28: PubMed Scopus Google Scholar), studies have the by insulin S. S. M. D. of insulin the of in A and PubMed Scopus Google Scholar, J. T. Y. K. D. The forkhead transcription factor adipocyte Cell. 2003; 4: Full Text Full Text PDF PubMed Scopus Google Scholar, H. T. K. A. N. Y. J. Y. J. role of insulin receptor 1 and in adipocyte Cell. Biol. PubMed Scopus Google Scholar). Both and insulin receptor are in the of preadipocytes K. 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Glucose-dependent insulinotropic polypeptide adipocyte development and glucose in through 2007; Full Text Full Text PDF PubMed Scopus Google Scholar) GIPR expression was to in the and this for the for of insulin both GIPR mRNA and protein levels increased during that insulin a role in regulating GIPR expression. GIP differentiation, it is to its synergistic effects on GIPR mRNA levels were effects of GIP on gene transcription or to the progression of Additionally, as both insulin and as well as are in during D. M. S.J. and function of growth factor during of J. PubMed Scopus Google Scholar), signaling involved in regulating GIPR expression during development of the adipocyte phenotype. A number of transcription for adipocyte have been PPARγ and of the binding protein and important of these during adipogenesis in increased expression of target protein expression is increased by GIP L. J. Glucose-dependent insulinotropic polypeptide adipocyte development and glucose in through 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). to the of PPARγ and in GIPR expression there was evidence that these transcription such a role in D. M. N. J.L. and of GIP receptor expression in by PPARγ mechanism for the GIP in 2 2010; PubMed Scopus Google Scholar, Pospisilik J.A. J.A. N. McIntosh C.H.S. Pederson R.A. A for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta J. 2003; PubMed Scopus Google Scholar, N. McIntosh C.H.S. Kieffer T.J. Pederson R.A. glucose-dependent insulinotropic polypeptide receptor expression in PubMed Scopus Google Scholar, G. H. N. K. S. of GLP-1 and GIP receptor expression by to incretin effects in 2007; PubMed Scopus Google Scholar). Additionally, was insulin is an of increasing its adipocyte expression through a B. regulation of sterol regulatory expression in and Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) and its M.B. the of nuclear sterol regulatory protein by downregulation of and its protein Biol. Chem. 2009; 284: Full Text Full Text PDF PubMed Scopus Google Scholar). In been shown to the of for PPARγ and regulate its M. through the of Sci. A. PubMed Scopus Google Scholar). was in 3T3-L1 levels not with the progression of or in GIPR expression. In both and PPARγ nuclear protein levels were increased by in a manner by of 3T3-L1 cell differentiation, and these were associated with increased GIPR expression. studies that selective of PPARγ a functional of PPARγ in the regulation of the GIPR gene expression. The PPARγ GW9662 ablated increases in GIPR protein and nuclear PPARγ and reduced GIPR mRNA levels and was a central role for the transcription factor in the regulation of GIPR expression. between PPARγ and the GIPR was following GW9662 to the of of PPARγ expression its as GW9662 in a of in mRNA expression levels GW9662 is an of PPARγ D.J. J.L. L. of in the binding of peroxisome proliferator by 2002; PubMed Scopus Google Scholar), it is that binding in of core histone exert a regulatory effect on gene transcription by of transcription to target been shown to acetylated and whereas histone is acetylated and In histone acetylation was shown to increased during of 3T3-L1 and inhibition of histone adipocyte G. to histone 2009; PubMed Scopus Google Scholar, Kim Kim of histone adipocyte Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, D.J. M. T. J. M.A. of through an 2010; 24: PubMed Scopus Google Scholar). Additionally, both incretin hormones GIP and GLP-1 β-cell by histone acetylation S.J. Nian C. McIntosh C.H.S. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 beta-cell Biol. Chem. 2009; 284: Full Text Full Text PDF PubMed Scopus Google Scholar). In the acetylation of histone and histone increased during of 3T3-L1 with the of GIP insulin or insulin and PPARγ was shown to with the of the GIPR promoter with acetylated histones H3/H4 between PPARγ binding to the of the GIPR promoter and core histone to an important role in the regulation of adipocyte GIPR expression. A functional between PPARγ binding and adipocyte GIPR expression was by the reduced GIPR expression following of PPARγ In an study of it was shown that and the agonist GIPR gene and gene expression was reduced with a of Pospisilik J.A. J.A. N. McIntosh C.H.S. Pederson R.A. A for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in beta J. 2003; PubMed Scopus Google Scholar). was shown to for the effects of on β-cell incretin A. Drucker D.J. the incretin receptor via a dependent on peroxisome proliferator-activated in PubMed Scopus Google Scholar). In and D. M. N. J.L. and of GIP receptor expression in by PPARγ mechanism for the GIP in 2 2010; PubMed Scopus Google Scholar) evidence for PPARγ an important role in the regulation of β-cell GIPR expression. Both of the of the expression through binding to and with of the receptor of on mechanisms of 2005; PubMed Scopus Google Scholar). the 3T3-L1 cell evidence was for PPARγ not in regulation of the adipocyte GIPR gene expression, and studies are to both transcription are of regulating expression in the In GIP and insulin act in a synergistic manner on 3T3-L1 cell differentiation, and during this adipocyte GIPR expression is upregulated through interactions between PPARγ and the in the GIPR promoter containing highly acetylated In of the of long-acting and inhibitors for type 2 diabetes therapy and the of actions of GIP S.B. Kim S.J. Yang G.K. De Los Reyes T. Nian C. Asadi A. Seino Y. Kieffer T.J. Kwok Y.N. McIntosh C.H.S. A GIP receptor agonist exhibits β-cell anti-apoptotic actions in rat models of diabetes resulting in improved β-cell function and glycemic control.PLoS ONE. 2010; 5: e9590Crossref PubMed Scopus (81) Google Scholar), it is important to expression of the GIPR regulation and in with type 2 diabetes. with adipocyte factor response element binding protein 1c dipeptidyl peptidase-IV glucose-dependent insulinotropic polypeptide GIP receptor peroxisome proliferator-activated receptor γ glucagon-like peptide-1 growth peroxisome proliferator response element RNA

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