title: Dimethylfumarate suppresses adipogenic differentiation in 3T3-L1 preadipocytes through inhibition of STAT3 activity.
abstract: The excessive accumulation of adipocytes contributes to the development of obesity and obesity-related diseases. The interactions of several transcription factors, such as C/EBPβ, PPARγ, C/EBPα, Nrf2, and STAT3, are required for adipogenic differentiation. Dimethylfumarate (DMF), an immune modulator and antioxidant, may function as an inhibitor of STAT3 and an activator of Nrf2. This study examined whether DMF inhibits adipogenic differentiation of 3T3-L1 preadipocytes by inhibiting STAT3 or activating Nrf2. DMF suppressed 3T3-L1 preadipocyte differentiation to mature adipocytes in a dose-dependent manner as determined by Oil Red O staining. The mRNA and protein levels of adipogenic genes, including C/EBPβ, C/EBPα, PPARγ, SREBP-1c, FAS, and aP2, were significantly lower in DMF-treated 3T3-L1 preadipocytes. Suppression of adipogenic differentiation by DMF treatment resulted primarily from inhibition of the early stages of differentiation. DMF inhibits clonal expansion during adipogenic differentiation through induction of a G1 cell cycle arrest. Additionally, DMF regulates cell cycle-related proteins, such as p21, pRb, and cyclin D. DMF treatment markedly inhibited differentiation medium-induced STAT3 phosphorylation and inhibited STAT3 transcriptional activation of a reporter construct composed of four synthetic STAT3-response elements. Moreover, inhibition of endogenous Nrf2 activity using a dominant negative Nrf2 did not abolish the DMF-induced inhibition of adipogenic differentiation of 3T3-L1 preadipocytes. In summary, DMF is a negative regulator of adipogenic differentiation based on its regulation of adipogenic transcription factors and cell cycle proteins. This negative regulation by DMF is mediated by STAT3 inhibition, but is unlikely to involve Nrf2 activation.
authors: Department of Biomedical Science, Graduate School, Kyungpook National University, Daegu, Republic of Korea.
authors: Hyeon-Ji
authors: HJ
authors: Kang
authors: Hyun-Ae
authors: HA
authors: Seo
authors: Younghoon
authors: Y
authors: Go
authors: Chang Joo
authors: CJ
authors: Oh
authors: Nam Ho
authors: NH
authors: Jeoung
authors: Keun-Gyu
authors: KG
authors: Park
authors: In-Kyu
authors: IK
authors: Lee
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D000069462:Dimethyl Fumarate; D005650:Fumarates / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D005650:Fumarates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D050796:STAT3 Transcription Factor; D000069462:Dimethyl Fumarate
references: Swiss Med Wkly. 2010 Dec 07;140:w13132
references: 21136335
references: Prostaglandins Leukot Essent Fatty Acids. 2005 Jul;73(1):31-4
references: 15936931
references: Nat Rev Mol Cell Biol. 2011 Sep 28;12(11):722-34
references: 21952300
references: Proc Natl Acad Sci U S A. 1991 Mar 15;88(6):2593-7
references: 2006196
references: Genes Dev. 2000 Jun 1;14(11):1293-307
references: 10837022
references: Endocrinology. 2000 Jul;141(7):2370-6
references: 10875236
references: J Am Acad Dermatol. 1994 Jun;30(6):977-81
references: 8188891
references: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8757-61
references: 8090719
references: Br J Dermatol. 1999 Sep;141(3):424-9
references: 10584060
references: Diabetes. 2012 Dec;61(12):3208-18
references: 22936178
references: Brain. 2011 Mar;134(Pt 3):678-92
references: 21354971
references: Biochem Biophys Res Commun. 1997 Nov 7;240(1):99-103
references: 9367890
references: PLoS Comput Biol. 2009 Mar;5(3):e1000324
references: 19325873
references: Biol Cell. 2009 Sep 23;102(1):1-12
references: 19566485
references: J Biol Chem. 1998 Nov 13;273(46):30057-60
references: 9804754
references: FEBS Lett. 1996 Oct 7;394(3):365-70
references: 8830676
references: Lancet. 2008 Oct 25;372(9648):1463-72
references: 18970976
references: N Engl J Med. 2012 Sep 20;367(12):1098-107
references: 22992073
references: J Biol Chem. 2000 Jun 23;275(25):18794-800
references: 10764767
references: Oncogene. 2000 May 15;19(21):2548-56
references: 10851053
references: Dig Dis Sci. 2009 Sep;54(9):1847-56
references: 19052866
references: PLoS One. 2012;7(10):e45870
references: 23056222
references: Int J Mol Med. 2011 Nov;28(5):823-8
references: 21805027
references: J Neuroinflammation. 2010 May 19;7:30
references: 20482831
references: Annu Rev Pharmacol Toxicol. 1999;39:295-312
references: 10331086
references: Genes Dev. 1999 Jun 15;13(12):1501-12
references: 10385618
references: PLoS One. 2011 Jan 31;6(1):e16172
references: 21297955
references: Mol Cell Biol. 2007 Oct;27(20):7188-97
references: 17709388
references: Physiol Rev. 1998 Jul;78(3):783-809
references: 9674695
references: Obes Res. 2002 Dec;10 Suppl 2:97S-104S
references: 12490658
references: J Exp Med. 2011 Oct 24;208(11):2291-303
references: 21987655
references: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):44-9
references: 12502791
references: Biochem Biophys Res Commun. 1995 Apr 6;209(1):40-6
references: 7726861
references: J Biol Chem. 1997 Feb 28;272(9):5367-70
references: 9102400
references: J Biol Chem. 2009 May 15;284(20):13291-5
references: 19182219
references: N Engl J Med. 2012 Sep 20;367(12):1087-97
references: 22992072
references: Curr Opin Cell Biol. 1996 Dec;8(6):826-32
references: 8939673
references: J Cell Biochem. 2011 Feb;112(2):488-97
references: 21268070
references: J Immunol. 2003 Mar 15;170(6):3263-72
references: 12626585