Targeted deletion of Tcf7l2 in adipocytes promotes adipocyte hypertrophy and impaired glucose metabolism.
Adipose tissue
Diabetes
Lipolysis
Obesity
Wnt signaling
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
29
11
2018
revised:
02
03
2019
accepted:
09
03
2019
pubmed:
6
4
2019
medline:
16
4
2020
entrez:
6
4
2019
Statut:
ppublish
Résumé
Activation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism. We generated Tcf7l2 Here we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue. Together our studies support that TCF7L2 is a central transcriptional regulator of the adipocyte metabolic program by directly regulating the expression of genes involved in lipid and glucose metabolism.
Identifiants
pubmed: 30948248
pii: S2212-8778(18)31029-9
doi: 10.1016/j.molmet.2019.03.003
pmc: PMC6531814
pii:
doi:
Substances chimiques
Tcf7l2 protein, mouse
0
Transcription Factor 7-Like 2 Protein
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
44-63Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK103930
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007115
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK097285
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK103089
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020579
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK091317
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier GmbH.
Références
Acta Diabetol. 2013 Oct;50(5):789-99
pubmed: 22843023
Eur J Obstet Gynecol Reprod Biol. 2014 Sep;180:77-82
pubmed: 25048152
Diabetes. 2008 Mar;57(3):645-53
pubmed: 18071026
Prostate. 2008 May 15;68(7):740-7
pubmed: 18302196
PLoS One. 2013;8(4):e60212
pubmed: 23577093
Diabetes. 2007 Oct;56(10):2631-7
pubmed: 17579206
Metabolism. 2007 Sep;56(9):1174-8
pubmed: 17697858
Diabetes. 2018 Apr;67(4):554-568
pubmed: 29317436
Exp Clin Endocrinol Diabetes. 2012 Sep;120(8):466-8
pubmed: 22441719
J Clin Endocrinol Metab. 2011 Feb;96(2):E389-93
pubmed: 21159844
Pharmacol Rep. 2011;63(3):826-33
pubmed: 21857094
J Diabetes Metab Disord. 2016 Mar 01;15:4
pubmed: 26937418
Mutagenesis. 2013 Jan;28(1):25-37
pubmed: 23188737
Afr Health Sci. 2015 Dec;15(4):1149-60
pubmed: 26958016
Gene. 2014 Jan 10;533(2):554-7
pubmed: 24157263
Hum Reprod Update. 2013 Jul-Aug;19(4):376-90
pubmed: 23690305
Diabetes Metab Res Rev. 2010 May;26(4):261-70
pubmed: 20503258
Cell Metab. 2010 Mar 3;11(3):183-93
pubmed: 20197051
Ann Hum Genet. 2015 Sep;79(5):373-379
pubmed: 26155736
Mamm Genome. 2012 Oct;23(9-10):680-92
pubmed: 22892838
Zhonghua Fu Chan Ke Za Zhi. 2014 Aug;49(8):588-93
pubmed: 25354859
Scand J Clin Lab Invest. 2009;69(2):282-7
pubmed: 18972257
Cancer Causes Control. 2008 Nov;19(9):975-80
pubmed: 18478343
Diabetes. 2007 Feb;56(2):389-93
pubmed: 17259383
Cell. 1982 Nov;31(1):99-109
pubmed: 6297757
Genet Mol Res. 2014 Sep 29;13(3):7889-98
pubmed: 25299103
Eur J Hum Genet. 2010 Dec;18(12):1333-8
pubmed: 20648057
Diabetes Res Clin Pract. 2009 Aug;85(2):139-46
pubmed: 19482368
Diabet Med. 2011 Sep;28(9):1018-27
pubmed: 21672010
Cell Metab. 2011 Apr 6;13(4):413-427
pubmed: 21459326
Indian J Med Res. 2011 Mar;133:294-9
pubmed: 21441683
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Gene. 2013 Jan 25;513(2):244-8
pubmed: 23142382
Diabetologia. 2009 Apr;52(4):614-20
pubmed: 19183934
Science. 2000 Aug 11;289(5481):950-3
pubmed: 10937998
BMC Med Genet. 2008 Aug 16;9:80
pubmed: 18706099
Int J Environ Res Public Health. 2015 Sep 18;12(9):11797-814
pubmed: 26393635
ScientificWorldJournal. 2014;2014:650393
pubmed: 25121131
J Biol Chem. 2007 Mar 16;282(11):8027-35
pubmed: 17237500
Cell. 2012 Dec 21;151(7):1595-607
pubmed: 23260145
J Biol Chem. 2002 Jan 18;277(3):1884-91
pubmed: 11711551
BMC Res Notes. 2015 Nov 25;8:717
pubmed: 26608632
Diabetes. 2006 Sep;55(9):2645-8
pubmed: 16936216
J Clin Endocrinol Metab. 2010 Mar;95(3):1450-7
pubmed: 20097709
Diabetologia. 2007 May;50(5):980-4
pubmed: 17340123
Obesity (Silver Spring). 2012 Jun;20(6):1273-8
pubmed: 22301903
Physiol Res. 2012;61(3):229-40
pubmed: 22480428
Clin Biochem. 2015 Nov;48(16-17):1064-7
pubmed: 26102344
Nat Genet. 2007 Feb;39(2):218-25
pubmed: 17206141
Diabetes. 2006 Sep;55(9):2649-53
pubmed: 16936217
Genet Mol Biol. 2010 Jul;33(3):449-51
pubmed: 21637413
Genet Mol Res. 2015 Aug 21;14(3):10064-71
pubmed: 26345943
Cell. 2012 Jun 8;149(6):1245-56
pubmed: 22682247
Science. 1995 Jul 28;269(5223):543-6
pubmed: 7624777
Breast Cancer Res Treat. 2012 Nov;136(2):593-602
pubmed: 23085767
Nature. 1998 Oct 8;395(6702):604-8
pubmed: 9783586
BMC Cancer. 2009 Sep 04;9:312
pubmed: 19732438
Diabetes Res Clin Pract. 2012 Dec;98(3):e23-7
pubmed: 23107111
Proc Natl Acad Sci U S A. 2017 Sep 5;114(36):E7469-E7478
pubmed: 28827348
Diabetes. 2011 Feb;60(2):662-8
pubmed: 20980453
Diabetol Metab Syndr. 2009 Oct 12;1(1):16
pubmed: 19825152
Diabetes. 2006 Sep;55(9):2654-9
pubmed: 16936218
Science. 1997 Mar 21;275(5307):1787-90
pubmed: 9065402
Diabetes. 2010 Aug;59(8):2068-74
pubmed: 20424228
Obesity (Silver Spring). 2008 Feb;16(2):476-82
pubmed: 18239663
Diabetes. 2007 Aug;56(8):2178-82
pubmed: 17519421
Pediatr Diabetes. 2017 Dec;18(8):824-831
pubmed: 28101933
Genes Nutr. 2016 Mar 21;11:6
pubmed: 27551309
Diabetes Metab J. 2015 Dec;39(6):512-7
pubmed: 26616591
Diabetes. 2006 Oct;55(10):2903-8
pubmed: 17003360
BMC Med Genet. 2008 Jul 26;9:72
pubmed: 18655717
N Engl J Med. 2006 Jul 20;355(3):241-50
pubmed: 16855264
BMC Cancer. 2006 Nov 17;6:268
pubmed: 17109766
Arch Med Res. 2011 Aug;42(6):495-501
pubmed: 22136959
Diabetes. 2007 Feb;56(2):295-303
pubmed: 17259372
Diabetologia. 2007 Dec;50(12):2443-50
pubmed: 17661009
Diabetologia. 2007 Apr;50(4):747-51
pubmed: 17245589
Eur Rev Med Pharmacol Sci. 2015 Aug;19(16):3100-6
pubmed: 26367734
Cell Metab. 2018 Jul 03;28(1):45-54.e3
pubmed: 29861390
Circ Res. 2018 Jun 22;123(1):73-85
pubmed: 29691232
Diabetes. 2007 May;56(5):1481-5
pubmed: 17317761
Diabetologia. 2007 Jan;50(1):63-7
pubmed: 17093941
Hum Mol Genet. 2009 Oct 15;18(20):3795-804
pubmed: 19602480
Cell. 2014 Jul 3;158(1):41-53
pubmed: 24995977
Biochem Genet. 2012 Apr;50(3-4):159-79
pubmed: 21898192
J Clin Invest. 2007 Aug;117(8):2155-63
pubmed: 17671651
Horm Metab Res. 2007 Jan;39(1):46-52
pubmed: 17226113
Diabetes Metab Res Rev. 2014 Nov;30(8):701-6
pubmed: 24639413
Diabetologia. 2011 Mar;54(3):535-9
pubmed: 21109996
Diabetologia. 2009 Feb;52(2):253-61
pubmed: 19002430
J Hepatol. 2013 Feb;58(2):271-7
pubmed: 23041303
Am J Clin Nutr. 2009 Apr;89(4):1256-62
pubmed: 19211816
Cell Metab. 2015 Feb 3;21(2):334-347
pubmed: 25651185
Diabetes. 2006 Dec;55(12):3630-4
pubmed: 17130514
Diabetologia. 2008 Nov;51(11):1993-7
pubmed: 18712344
Diabetologia. 2008 Jan;51(1):62-9
pubmed: 17972059
Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):6991-5
pubmed: 7624356
Genes Dev. 2017 Feb 15;31(4):336-346
pubmed: 28314766
Nutr Metab Cardiovasc Dis. 2013 Jun;23(6):550-6
pubmed: 22402060
Ann Nutr Metab. 2015;67(4):228-35
pubmed: 26536002
Genetika. 2010 Aug;46(8):1123-31
pubmed: 20873210
Br J Nutr. 2016 Sep;116(6):969-78
pubmed: 27480250
Nat Genet. 2006 Mar;38(3):320-3
pubmed: 16415884
Diabetes. 2006 Oct;55(10):2890-5
pubmed: 17003358
Braz J Med Biol Res. 2013 Apr;46(4):382-93
pubmed: 23579632
J Biol Chem. 1995 Nov 10;270(45):26746-9
pubmed: 7592907
Genet Mol Biol. 2012 Apr;35(2):413-7
pubmed: 22888288
Clin Transl Med. 2015 Apr 23;4:17
pubmed: 25995831
Diabetologia. 2007 Jan;50(1):1-4
pubmed: 17096114
J Lipid Res. 2016 Jun;57(6):925-42
pubmed: 27099397
Bone. 2012 Feb;50(2):477-89
pubmed: 21872687
PLoS One. 2010 Mar 26;5(3):e9903
pubmed: 20361036
J Clin Endocrinol Metab. 2009 Feb;94(2):504-10
pubmed: 19050058
J Nutr. 2009 Mar;139(3):439-46
pubmed: 19141698
Diabetologia. 2007 Jan;50(1):59-62
pubmed: 17031610
PLoS One. 2011 Mar 15;6(3):e17978
pubmed: 21423583
Diabetologia. 2007 Sep;50(9):1852
pubmed: 17618413
Turk J Med Sci. 2016 Feb 27;47(1):22-28
pubmed: 28263491
Diabetologia. 2007 Nov;50(11):2318-22
pubmed: 17805508
Am J Clin Nutr. 2012 Nov;96(5):1129-36
pubmed: 23034957
J Mol Med (Berl). 2006 Dec;84(12):1005-14
pubmed: 17665514
Diabetologia. 2007 Jun;50(6):1186-91
pubmed: 17429603
Diabetes Res Clin Pract. 2016 Nov;121:35-40
pubmed: 27639123
Nucleic Acids Res. 2009 Jan;37(1):1-13
pubmed: 19033363
Diabetes. 2010 Mar;59(3):747-50
pubmed: 20028944
Diabetologia. 2008 Jun;51(6):968-70
pubmed: 18437354
Diabetes. 2007 Oct;56(10):2638-42
pubmed: 17601994
Exp Ther Med. 2016 Sep;12(3):1849-1856
pubmed: 27588103
Ann Hum Genet. 2011 Sep;75(5):612-20
pubmed: 21834909
BMC Bioinformatics. 2008 Dec 29;9:559
pubmed: 19114008
Diabetologia. 2016 Dec;59(12):2613-2621
pubmed: 27623947
Genome Res. 2011 Sep;21(9):1417-25
pubmed: 21673050
Diabetes Res Clin Pract. 2008 Jun;80(3):392-8
pubmed: 18282631
Cell Metab. 2013 Jan 8;17(1):141-52
pubmed: 23312289
Clin Lab. 2014;60(8):1269-76
pubmed: 25185411
Diabetes Care. 2008 Jan;31(1):63-8
pubmed: 17934151
J Diabetes Investig. 2017 Jul;8(4):560-570
pubmed: 28002648
Acta Diabetol. 2016 Dec;53(6):915-923
pubmed: 27488727
Diabetologia. 2007 Jun;50(6):1192-200
pubmed: 17437080
Braz J Med Biol Res. 2011 Mar;44(3):240-4
pubmed: 21399856
Diabet Med. 2010 Jun;27(6):701-4
pubmed: 20546291
Diabetologia. 2008 Jul;51(7):1146-52
pubmed: 18493736
Nature. 1996 Aug 15;382(6592):638-42
pubmed: 8757136
Diabetologia. 2007 Aug;50(8):1621-30
pubmed: 17579832
Diabetologia. 2012 Feb;55(2):349-57
pubmed: 22052079
Gynecol Endocrinol. 2017 May;33(5):399-404
pubmed: 28277135
Sci Rep. 2017 Feb 21;7:43128
pubmed: 28220878
Eur J Hum Genet. 2007 Mar;15(3):342-6
pubmed: 17245407
Cell Metab. 2011 Mar 2;13(3):249-59
pubmed: 21356515
Semin Cancer Biol. 2001 Feb;11(1):15-23
pubmed: 11243895
Diabetes Res Clin Pract. 2011 Nov;94(2):e43-6
pubmed: 21855162
J Hum Genet. 2008;53(2):174-180
pubmed: 18097733
Clin Genet. 2007 Apr;71(4):359-66
pubmed: 17470138
BMC Med Genet. 2009 Feb 19;10:15
pubmed: 19228405
J Biol Chem. 2005 Jun 24;280(25):24004-10
pubmed: 15849360
Diabetes. 2006 Sep;55(9):2640-4
pubmed: 16936215
Hum Mol Genet. 2014 Dec 15;23(24):6419-31
pubmed: 25015099
Arch Iran Med. 2015 Jun;18(6):376-8
pubmed: 26058934
Diabetes. 2009 Feb;58(2):493-8
pubmed: 19033397
Exp Clin Endocrinol Diabetes. 2009 Apr;117(4):186-90
pubmed: 19053027
PLoS One. 2013;8(3):e59495
pubmed: 23527206
BMC Med Genet. 2008 Feb 21;9:8
pubmed: 18291022
PLoS One. 2009 Sep 30;4(9):e7231
pubmed: 19789636
Exp Ther Med. 2017 Feb;13(2):523-529
pubmed: 28352326
Diabetes. 2007 Dec;56(12):3082-8
pubmed: 17909099
Arch Endocrinol Metab. 2015 Jul 21;60(3):246-51
pubmed: 26201011
Mol Cell Biol. 2012 May;32(10):1918-27
pubmed: 22393260
Nature. 2001 Jan 18;409(6818):307-12
pubmed: 11201732