title: PPARγ signaling and metabolism: the good, the bad and the future.
abstract: Thiazolidinediones (TZDs) are potent insulin sensitizers that act through the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) and are highly effective oral medications for type 2 diabetes. However, their unique benefits are shadowed by the risk for fluid retention, weight gain, bone loss and congestive heart failure. This raises the question as to whether it is possible to build a safer generation of PPARγ-specific drugs that evoke fewer side effects while preserving insulin-sensitizing potential. Recent studies that have supported the continuing physiologic and therapeutic relevance of the PPARγ pathway also provide opportunities to develop newer classes of molecules that reduce or eliminate adverse effects. This review highlights key advances in understanding PPARγ signaling in energy homeostasis and metabolic disease and also provides new explanations for adverse events linked to TZD-based therapy.
authors: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors: Maryam
authors: M
authors: Ahmadian
authors: Jae Myoung
authors: JM
authors: Suh
authors: Nasun
authors: N
authors: Hah
authors: Christopher
authors: C
authors: Liddle
authors: Annette R
authors: AR
authors: Atkins
authors: Michael
authors: M
authors: Downes
authors: Ronald M
authors: RM
authors: Evans
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D047495:PPAR gamma / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D047495:PPAR gamma; D045162:Thiazolidinediones; D005346:Fibroblast Growth Factors
references: Cell Res. 2012 Oct;22(10):1416-8
references: 22710798
references: Hepatology. 2007 Aug;46(2):424-9
references: 17559148
references: Nature. 2008 Nov 20;456(7220):350-6
references: 19043829
references: J Pharm Pharmacol. 2012 Feb;64(2):161-71
references: 22221092
references: PLoS One. 2009;4(3):e4907
references: 19300518
references: PPAR Res. 2011;2011:867180
references: 22135675
references: Diabetes. 2000 Sep;49(9):1517-24
references: 10969836
references: Diabetes. 2002 Oct;51(10):2968-74
references: 12351435
references: Endocrinology. 1998 Jun;139(6):3030-3
references: 9607817
references: Diabetes. 2003 Apr;52(4):910-7
references: 12663460
references: Wiley Interdiscip Rev Syst Biol Med. 2011 Sep-Oct;3(5):562-87
references: 21755605
references: Diabetes Care. 2005 Jul;28(7):1547-54
references: 15983299
references: Obesity (Silver Spring). 2009 Feb;17(2):213-9
references: 19169221
references: J Cell Physiol. 2012 Jun;227(6):2632-44
references: 21882190
references: Diabetes Care. 2007 Oct;30(10):2458-64
references: 17595355
references: Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11513-8
references: 10500208
references: Mol Neurobiol. 2012 Aug;46(1):114-24
references: 22434581
references: Am Heart J. 2008 Apr;155(4):712-7
references: 18371481
references: Diabetologia. 2012 Jul;55(7):1953-62
references: 22460763
references: Am J Clin Nutr. 2010 Jan;91(1):254S-257S
references: 19906798
references: Transcription. 2012 Jan-Feb;3(1):19-24
references: 22456316
references: J Lipid Res. 1999 Jul;40(7):1177-84
references: 10393202
references: Nature. 2005 Sep 29;437(7059):759-63
references: 16127449
references: Mol Cell Biol. 2010 May;30(9):2078-89
references: 20176806
references: Cell Metab. 2010 Apr 7;11(4):268-72
references: 20374959
references: J Biol Chem. 1995 Jun 2;270(22):12953-6
references: 7768881
references: Cell Metab. 2011 Jul 6;14(1):116-22
references: 21723509
references: Cell Metab. 2012 Mar 7;15(3):279-91
references: 22405066
references: Nat Med. 2011 May;17(5):618-22
references: 21532596
references: Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15712-7
references: 14660788
references: Heart. 2009 Jun;95(12):1020-2
references: 19478113
references: Diabetes. 2002 Mar;51(3):797-802
references: 11872682
references: Diabetes Obes Metab. 2010 Sep;12(9):806-14
references: 20649633
references: Diabetologia. 2012 Apr;55(4):885-904
references: 22278337
references: Expert Opin Drug Saf. 2012 Jul;11(4):565-79
references: 22616948
references: Am J Clin Nutr. 2010 Jan;91(1):267S-272S
references: 19906796
references: Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4543-7
references: 15070754
references: J Biol Chem. 1997 Feb 21;272(8):5283-90
references: 9030601
references: J Clin Invest. 2004 Mar;113(6):846-55
references: 15067317
references: Trends Endocrinol Metab. 2009 Nov;20(9):424-8
references: 19796963
references: JAMA. 2010 Jul 28;304(4):411-8
references: 20584880
references: BMC Genomics. 2011 Mar 16;12:152
references: 21410980
references: J Biol Chem. 1997 Apr 18;272(16):10811-6
references: 9099735
references: Genes Dev. 2008 Nov 1;22(21):2941-52
references: 18981473
references: Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8250-5
references: 18550844
references: Nat Med. 2005 Aug;11(8):861-6
references: 16007095
references: BMJ. 2012 May 30;344:e3645
references: 22653981
references: Diabetes. 1996 Nov;45(11):1572-9
references: 8866563
references: Immunity. 2010 Nov 24;33(5):699-712
references: 21093321
references: Physiol Behav. 2006 Jun 30;88(3):227-33
references: 16777151
references: Cell. 1998 Apr 17;93(2):241-52
references: 9568716
references: PPAR Res. 2010;2010:
references: 20706670
references: World J Gastroenterol. 2008 Jan 7;14(1):22-8
references: 18176957
references: J Biol Chem. 2000 Jun 16;275(24):18527-33
references: 10748014
references: Proteomics. 2003 Aug;3(8):1500-20
references: 12923776
references: J Clin Invest. 1997 Dec 1;100(11):2900-8
references: 9389757
references: Nat Med. 2003 Dec;9(12):1491-7
references: 14625542
references: Trends Endocrinol Metab. 2002 Oct;13(8):331-5
references: 12217489
references: Nature. 2010 Jul 22;466(7305):451-6
references: 20651683
references: Mol Cell Biol. 2003 Oct;23(20):7222-9
references: 14517292
references: EMBO J. 2011 Apr 20;30(8):1459-72
references: 21427703
references: Diabetes. 2003 Sep;52(9):2249-59
references: 12941763
references: Science. 1996 Dec 20;274(5295):2100-3
references: 8953045
references: J Biol Chem. 2003 Sep 5;278(36):34268-76
references: 12805374
references: PLoS Genet. 2007 Apr 27;3(4):e64
references: 17465682
references: Cardiovasc Ther. 2011 Dec;29(6):377-84
references: 20840193
references: Cell. 2012 Aug 3;150(3):620-32
references: 22863012
references: N Engl J Med. 2007 Jun 14;356(24):2457-71
references: 17517853
references: Physiol Rev. 2004 Jan;84(1):277-359
references: 14715917
references: Science. 2008 Oct 24;322(5901):583-6
references: 18801968
references: J Clin Invest. 2003 Aug;112(4):608-18
references: 12925701
references: Endocrinology. 1994 Jan;134(1):264-70
references: 8275942
references: Pharmacol Res. 2007 Aug;56(2):91-8
references: 17428674
references: Nucleic Acids Res. 2012 Sep 1;40(17):8255-65
references: 22730288
references: Annu Rev Biochem. 2008;77:289-312
references: 18518822
references: Sci STKE. 2002 Feb 26;2002(121):pe9
references: 11867819
references: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22504-9
references: 20018750
references: Mol Endocrinol. 2006 Jul;20(7):1494-505
references: 16484339
references: Mol Cell. 1999 Oct;4(4):585-95
references: 10549290
references: Nat Rev Mol Cell Biol. 2001 Oct;2(10):749-59
references: 11584302
references: Cell. 1994 Dec 30;79(7):1147-56
references: 8001151
references: Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4312-7
references: 9113986
references: Nature. 2012 Jun 28;486(7404):549-53
references: 22722857
references: N Engl J Med. 1998 Oct 1;339(14):953-9
references: 9753710
references: Endocrinology. 2001 Mar;142(3):1269-77
references: 11181544
references: Cell. 1998 Apr 17;93(2):229-40
references: 9568715
references: Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9406-11
references: 15956187
references: Nat Med. 2001 Jan;7(1):48-52
references: 11135615
references: Dev Cell. 2003 Oct;5(4):657-63
references: 14536066
references: Nature. 2011 Sep 04;477(7365):477-81
references: 21892191
references: Int J Obes (Lond). 2008 Sep;32 Suppl 4:S7-12
references: 18719601
references: Genes Dev. 1996 Apr 15;10(8):974-84
references: 8608944
references: Endocrinology. 2009 Feb;150(2):707-12
references: 18845632
references: Diabetes Metab Res Rev. 2007 Jul;23(5):392-9
references: 17211855
references: J Biol Chem. 2010 Mar 5;285(10):7153-64
references: 20028987
references: Cell Metab. 2011 May 4;13(5):495-504
references: 21531332
references: Ann N Y Acad Sci. 2006 Nov;1088:207-18
references: 17192567
references: J Clin Invest. 2007 Jun;117(6):1658-69
references: 17525798
references: Semin Cell Dev Biol. 2012 Aug;23(6):631-9
references: 22273692
references: Diabetes. 2003 Jun;52(6):1311-8
references: 12765938
references: J Clin Endocrinol Metab. 2002 Jan;87(1):408-11
references: 11788685
references: Mol Cell Biol. 2000 Mar;20(6):2260-8
references: 10688672
references: Cell. 1995 Dec 1;83(5):803-12
references: 8521497
references: J Biol Chem. 2001 Mar 9;276(10):7062-8
references: 11106650
references: Nature. 2007 Jun 28;447(7148):1116-20
references: 17515919
references: Structure. 2012 Jan 11;20(1):139-50
references: 22244763
references: Am Heart J. 2012 Nov;164(5):672-80
references: 23137497
references: JAMA. 2007 Sep 12;298(10):1180-8
references: 17848652
references: Am J Physiol Renal Physiol. 2012 Mar 1;302(5):F540-51
references: 22169011
references: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3143-8
references: 22315431
references: Nat Med. 2007 Dec;13(12):1496-503
references: 18059282
references: Nat Med. 2011 May;17(5):623-6
references: 21532595
references: Diabetes. 2003 Jul;52(7):1655-63
references: 12829629
references: Trends Endocrinol Metab. 2012 May;23(5):205-15
references: 22513163
references: FEBS Lett. 2011 Jul 7;585(13):2121-8
references: 21605560
references: J Biol Chem. 2009 Mar 6;284(10):6116-25
references: 19126543
references: Nat Med. 2005 Aug;11(8):875-9
references: 16007097
references: Diabetes. 2002 Mar;51(3):676-85
references: 11872666
references: Biochem Biophys Res Commun. 2000 Nov 30;278(3):704-11
references: 11095972
references: Biochim Biophys Acta. 2005 May 30;1740(2):293-304
references: 15949696
references: Scand J Gastroenterol. 2009;44(3):358-65
references: 18991162
references: J Clin Invest. 2006 Mar;116(3):590-7
references: 16511591
references: Nat Med. 2004 Apr;10(4):355-61
references: 15057233
references: Nat Rev Genet. 2010 Jul;11(7):476-86
references: 20531367
references: Diabetes. 2002 Dec;51(12):3586-90
references: 12453919
references: Nature. 1997 Mar 27;386(6623):407-10
references: 9121558
references: Circ Res. 2005 Aug 19;97(4):372-9
references: 16051889
references: Nature. 2012 May 17;485(7398):391-4
references: 22522926
references: Biochim Biophys Acta. 2007 Aug;1771(8):1014-30
references: 17418635
references: Ann N Y Acad Sci. 1996 Dec 27;804:266-75
references: 8993549
references: Cell Metab. 2012 Mar 7;15(3):395-404
references: 22405074
references: Chem Rev. 2011 Oct 12;111(10):6321-40
references: 21988241
references: J Biol Chem. 2009 Jan 23;284(4):2275-84
references: 19049962
references: Nat Med. 2012 Dec;18(12):1847-56
references: 23142820
references: Mol Cell Biochem. 2006 Jun;286(1-2):33-42
references: 16534556
references: J Biol Chem. 2008 Nov 21;283(47):32462-70
references: 18718916
references: J Biol Chem. 1996 Dec 13;271(50):31771-4
references: 8943212
references: Trends Endocrinol Metab. 2012 Jul;23(7):351-63
references: 22704720
references: Mol Cell Biol. 2005 Jul;25(14):6065-76
references: 15988019
references: J Clin Invest. 2007 Oct;117(10):2791-801
references: 17823655
references: Mutat Res. 2005 Dec 11;591(1-2):247-63
references: 16083919
references: Cell. 2012 Feb 3;148(3):556-67
references: 22304921
references: J Clin Invest. 2010 May;120(5):1454-68
references: 20364085