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.
Department of Cellular and Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Su-Jin
SJ
Kim
Cuilan
C
Nian
Christopher H S
CH
McIntosh
D041721:3T3-L1 Cells; D000107:Acetylation; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D006657:Histones / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism
D006657:Histones; D047495:PPAR gamma; D011964:Receptors, Gastrointestinal Hormone; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C041086:gastric inhibitory polypeptide receptor
Trends Pharmacol Sci. 2003 Mar;24(3):110-2
12628351
Mol Cell Biol. 2001 Apr;21(7):2521-32
11259600
Int J Biochem Cell Biol. 1996 May;28(5):499-510
8697095
J Biol Chem. 2007 Nov 23;282(47):34139-47
17890220
Endocrinology. 2004 Jun;145(6):2653-9
15044356
Clin Sci (Lond). 1997 Jan;92(1):3-11
9038586
Diabetes Care. 2005 May;28(5):1092-100
15855572
Proc Natl Acad Sci U S A. 1994 Mar 1;91(5):1786-90
8127882
Front Biosci. 2008 Jan 01;13:1753-73
17981665
Endocrinology. 2003 Oct;144(10):4433-45
12960055
J Lipid Res. 2007 Jun;48(6):1253-62
17374880
J Biol Chem. 2005 Jun 10;280(23):22297-307
15817464
Nat Rev Drug Discov. 2005 Sep;4(9):713-4
16178120
J Biol Chem. 2009 Nov 13;284(46):31726-34
19759400
Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4333-7
9539737
Diabetes Care. 2007 Feb;30(2):217-23
17259484
J Biol Chem. 2007 Mar 23;282(12):8557-67
17244606
Diabetologia. 2011 Feb;54(2):339-49
20972533
Diabetes. 2007 Jun;56(6):1551-8
17360984
Cell Metab. 2006 Nov;4(5):391-406
17084712
Diabetologia. 1998 Feb;41(2):171-7
9498650
J Histochem Cytochem. 2009 Aug;57(8):731-9
19365091
Nucleic Acids Res. 1989 Aug 11;17(15):6419
2771659
Diabetes. 2001 May;50(5):1004-11
11334402
Genes Dev. 2010 May 15;24(10):1035-44
20478996
Diabetes Care. 2004 Aug;27(8):1915-21
15277417
Expert Opin Investig Drugs. 2007 Apr;16(4):533-45
17371200
J Biol Chem. 2009 May 8;284(19):12896-904
19279000
Dev Cell. 2003 Jan;4(1):119-29
12530968
J Lipid Res. 2010 Nov;51(11):3145-57
20693566
J Clin Invest. 2007 Jan;117(1):24-32
17200703
Physiol Rev. 1998 Jul;78(3):783-809
9674695
Lancet. 2006 Nov 11;368(9548):1696-705
17098089
Diabetes. 2010 Jun;59(6):1445-50
20332343
Endocrinology. 1999 Jan;140(1):398-404
9886851
J Biol Chem. 2004 Aug 13;279(33):34380-7
15187085
J Biol Chem. 2006 Mar 10;281(10):6608-15
16407282
Neuropeptides. 2003 Oct;37(5):253-63
14607102
Science. 2009 May 22;324(5930):1076-80
19461003
Histochemistry. 1992 Jul;97(6):493-7
1385366
Mol Cell Biol. 2008 Mar;28(5):1644-56
18086876
Biochemistry. 2002 May 28;41(21):6640-50
12022867
Annu Rev Cell Dev Biol. 2000;16:145-71
11031233
Growth Horm IGF Res. 2009 Apr;19(2):101-11
18693051
FASEB J. 2003 Jan;17(1):91-3
12475913
J Biol Chem. 1988 Jul 5;263(19):9402-8
2967822
Nat Med. 2002 Jul;8(7):738-42
12068290
Gastroenterology. 2007 Dec;133(6):1796-805
18054552
J Biol Chem. 2009 Oct 30;284(44):30372-82
19748889
Vitam Horm. 2009;80:409-71
19251046
Int J Obes (Lond). 2008 Nov;32(11):1705-11
18779825
Pharmacol Res. 2005 Feb;51(2):85-94
15629253
Biochem J. 1998 Aug 1;333 ( Pt 3):825-31
9677346
PLoS One. 2010 Mar 09;5(3):e9590
20231880