PPARγ: a circadian transcription factor in adipogenesis and osteogenesis.
Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists, the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu-that is, increased bone marrow adiposity with suppression of osteogenesis-could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism.
Kawai
Masanobu
M
Center for Clinical and Translational Research, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074-7205, USA.
Rosen
Clifford J
CJ
D050156:Adipogenesis / Q000502:physiology*; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000187:drug effects; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D010012:Osteogenesis / Q000502:physiology*; D010024:Osteoporosis; D047495:PPAR gamma / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D009687:Nuclear Proteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D014157:Transcription Factors; C102804:nocturnin
J Biol Chem. 2002 Feb 8;277(6):4062-8
11733495
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14884-8
8962150
J Cell Biochem. 1999 Sep 1;74(3):357-71
10412038
Nat Med. 2004 Apr;10(4):355-61
15057233
J Biol Chem. 2005 Apr 1;280(13):12867-75
15664998
Ann N Y Acad Sci. 2010 Mar;1192:131-8
20392228
J Biol Chem. 1998 Nov 13;273(46):30057-60
9804754
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9888-93
17517647
Cell. 2002 Jul 26;110(2):251-60
12150932
J Biol Chem. 2001 Oct 12;276(41):37731-4
11459852
J Cell Biochem. 2009 Feb 1;106(2):232-46
19115254
J Biol Chem. 2003 Jan 24;278(4):2581-4
12426306
Diabetes Care. 2007 Jun;30(6):1574-6
17363747
PLoS Biol. 2007 Feb;5(2):e34
17298173
Eur J Nutr. 2003 Apr;42(2):75-83
12638028
J Lipid Res. 2010 Aug;51(8):2352-61
20410018
J Biol Chem. 2003 Nov 14;278(46):45969-77
12925529
Am J Physiol Endocrinol Metab. 2010 Jul;299(1):E3-9
20407009
Mol Cell Biol. 2005 Jan;25(2):706-15
15632071
Cell Metab. 2010 Jun 9;11(6):503-16
20519122
BMC Genomics. 2001;2:9
11747467
J Clin Endocrinol Metab. 2006 Sep;91(9):3349-54
16608888
N Engl J Med. 2006 Dec 7;355(23):2427-43
17145742
Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10630-5
11535822
N Engl J Med. 2007 Aug 30;357(9):844-6
17687124
Eur J Clin Invest. 2007 Sep;37(9):709-14
17696960
J Clin Invest. 2004 Mar;113(6):846-55
15067317
J Biol Chem. 1997 Apr 18;272(16):10811-6
9099735
Cell. 2007 Aug 10;130(3):456-69
17693256
Cell Metab. 2008 Jan;7(1):7-10
18177720
Genes Cells. 2004 Nov;9(11):1017-29
15507114
J Clin Endocrinol Metab. 2010 Feb;95(2):592-600
20061432
J Biol Chem. 2000 Jun 16;275(24):18527-33
10748014
Genes Dev. 2005 Feb 15;19(4):453-61
15681609
Nat Rev Mol Cell Biol. 2006 Dec;7(12):885-96
17139329
Mol Cell. 1999 Mar;3(3):397-403
10198642
Nat Med. 2003 Dec;9(12):1491-7
14625542
Endocrinology. 2009 Mar;150(3):1330-40
18948404
Endocrinology. 1996 Jan;137(1):354-66
8536636
J Biol Chem. 2004 Aug 6;279(32):34015-22
15175325
Pediatr Nephrol. 2009 Jul;24(7):1277-85
19011906
Science. 1996 Dec 20;274(5295):2100-3
8953045
Cell. 2008 Sep 5;134(5):728-42
18775307
Science. 2005 May 13;308(5724):1043-5
15845877
J Biol Chem. 2003 Sep 5;278(36):34268-76
12805374
Cell. 2010 Jul 23;142(2):309-19
20655471
Obesity (Silver Spring). 2007 Mar;15(3):539-43
17372301
Endocrinology. 2004 Apr;145(4):1916-25
14715714
J Clin Invest. 2003 Aug;112(4):608-18
12925701
J Clin Invest. 1998 Mar 15;101(6):1354-61
9502777
Curr Opin Investig Drugs. 2009 Oct;10(10):1085-90
19777397
Annu Rev Biochem. 2008;77:289-312
18518822
Arch Intern Med. 2009 Aug 10;169(15):1395-402
19667303
Diabetes Care. 1992 Feb;15(2):193-203
1547676
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2443-8
11226258
Bone. 2006 Oct;39(4):796-806
16759917
N Engl J Med. 1994 Nov 3;331(18):1188-93
7935656
FEBS Lett. 2006 Jan 9;580(1):127-30
16343493
Curr Biol. 2003 Feb 4;13(3):189-98
12573214
Nature. 2010 Mar 25;464(7288):619-23
20200519
Genes Dev. 1994 May 15;8(10):1224-34
7926726
Bone. 1999 Oct;25(4):421-9
10511108
Diabetes Obes Metab. 2010 Aug;12(8):716-21
20590749
Nat Cell Biol. 2007 Nov;9(11):1273-85
17952062
J Cell Physiol. 2006 Dec;209(3):967-76
16972249
Diabetes Care. 2000 Aug;23(8):1067-71
10937499
Nat Rev Mol Cell Biol. 2007 Feb;8(2):139-48
17245414
Diabetes. 1988 Nov;37(11):1549-58
3053303
BMC Dev Biol. 2001;1:9
11394964
Cell. 2005 Sep 9;122(5):803-15
16143109
Science. 1990 Feb 23;247(4945):975-8
2305266
Nature. 2007 May 24;447(7143):477-81
17476214
Cell. 1995 Dec 1;83(5):803-12
8521497
Mol Cell. 1999 Oct;4(4):597-609
10549291
J Cell Biol. 2008 Dec 29;183(7):1235-42
19103808
Nat Med. 2007 Dec;13(12):1496-503
18059282
Cell. 2006 Aug 25;126(4):801-10
16923398
Lancet. 2009 Jun 20;373(9681):2125-35
19501900
Nature. 2009 Jul 9;460(7252):259-63
19516257
Calcif Tissue Int. 2004 Oct;75(4):329-37
15549648
J Clin Endocrinol Metab. 2007 Apr;92(4):1305-10
17264176
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10508-13
20498072
RNA. 2007 May;13(5):745-55
17400819
Nat Rev Neurosci. 2009 Aug;10(8):549-60
19617891
PLoS Biol. 2004 Nov;2(11):e377
15523558
Metabolism. 1990 Oct;39(10):1056-62
2120548
Bone. 2008 Apr;42(4):765-74
18242157
Diabetes Care. 2003 Nov;26(11):3148-52
14578253
Endocrinology. 2007 Feb;148(2):903-11
17122083
Cell. 2001 Feb 9;104(3):377-86
11239395
Science. 2000 Sep 29;289(5488):2344-7
11009419
Nat Med. 2008 Feb;14(2):188-93
18204460
Cell Metab. 2005 Jan;1(1):27-39
16054042
Cell. 2010 Jul 23;142(2):296-308
20655470
Diabetes Care. 1991 Nov;14(11):1083-6
1797492
Endocrinology. 2007 Jun;148(6):2669-80
17332064