title: Postnatal exposure to a high-carbohydrate diet interferes epigenetically with thyroid hormone receptor induction of the adult male rat skeletal muscle glucose transporter isoform 4 expression.
abstract: Early life nutritional intervention causes adult-onset insulin resistance and obesity in rats. Thyroid hormone receptor (TR), in turn, transcriptionally enhances skeletal muscle Glut4 expression. We tested the hypothesis that reduced circulating thyroid-stimulating hormone and T4 concentrations encountered in postnatal (PN4-PN24) high-carbohydrate (HC) milk formula-fed versus the mother-fed controls (MF) would epigenetically interfere with TR induction of adult (100 days) male rat skeletal muscle Glut4 expression, thereby providing a molecular mechanism mediating insulin resistance. We observed increased DNA methylation of the CpG island with enhanced recruitment of Dnmt3a, Dnmt3b and MeCP2 in the glut4 promoter region along with reduced acetylation of histone (H)2A.Z and H4 particularly at the H4.lysine (K)16 residue, which was predominantly mediated by histone deacetylase 4 (HDAC4). This was followed by enhanced recruitment of heterochromatin protein 1β to the glut4 promoter with increased Suv39H1 methylase concentrations. These changes reduced TR binding of the T3 response element of the glut4 gene (TREs; -473 to -450 bp) detected qualitatively in vivo (electromobility shift assay) and quantified ex vivo (chromatin immunoprecipitation). In addition, the recruitment of steroid receptor coactivator and CREB-binding protein to the glut4 promoter-protein complex was reduced. Co-immunoprecipitation experiments confirmed the interaction between TR and CBP to be reduced and HDAC4 to be enhanced in HC versus MF groups. These molecular changes were associated with diminished skeletal muscle Glut4 mRNA and protein concentrations. We conclude that early postnatal exposure to HC diet epigenetically reduced TR induction of adult male skeletal muscle Glut4 expression, uncovering novel molecular mechanisms contributing to adult insulin resistance and obesity.
authors.affiliation: Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA.
authors.forename: Nupur
authors.initials: N
authors.lastname: Raychaudhuri
authors.affiliation: Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA.
authors.forename: Shanthie
authors.initials: S
authors.lastname: Thamotharan
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
authors.forename: Malathi
authors.initials: M
authors.lastname: Srinivasan
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
authors.forename: Saleh
authors.initials: S
authors.lastname: Mahmood
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
authors.forename: Mulchand S
authors.initials: MS
authors.lastname: Patel
authors.affiliation: Department of Pediatrics, Division of Neonatology & Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA. Electronic address: sdevaskar@mednet.ucla.edu.
authors.forename: Sherin U
authors.initials: SU
authors.lastname: Devaskar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D044127:Epigenesis, Genetic; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D007333:Insulin Resistance; D008297:Male; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D011181:Postnatal Care; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000097:blood / Q000235:genetics*; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D004040:Dietary Carbohydrates; D051275:Glucose Transporter Type 4; D006657:Histones; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; C495694:Slc2a4 protein, rat; D014284:Triiodothyronine; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases; D013974:Thyroxine
keywords: DNA methylase; DNA methylation; High Carbohydrate programming; Histone code modifications; Histone deacetylase; Insulin resistance; Obesity
references.citation: Diabetes. 1994 Oct;43(10):1185-9
references.pmid: 7926286
references.citation: Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E792-9
references.pmid: 16720630
references.citation: Thyroid. 2008 Feb;18(2):239-53
references.pmid: 18279024
references.citation: Am J Physiol. 1993 Oct;265(4 Pt 1):E565-71
references.pmid: 8238331
references.citation: Genes Dev. 2004 Jun 1;18(11):1263-71
references.pmid: 15175259
references.citation: Int J Obes Relat Metab Disord. 1993 Sep;17(9):495-502
references.pmid: 8220651
references.citation: Cell. 2007 Feb 23;128(4):707-19
references.pmid: 17320508
references.citation: Cell. 1992 Jan 24;68(2):377-95
references.pmid: 1310259
references.citation: J Endocrinol. 2008 Jun;197(3):565-74
references.pmid: 18492820
references.citation: Biochim Biophys Acta. 1990 Dec 11;1032(2-3):157-76
references.pmid: 2261492
references.citation: Am J Physiol. 1998 Feb;274(2):E287-96
references.pmid: 9486160
references.citation: Int J Obes. 1977;1(2):185-90
references.pmid: 82548
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4070-5
references.pmid: 10737771
references.citation: J Biol Chem. 2004 Jun 18;279(25):26768-79
references.pmid: 15054091
references.citation: J Physiol. 2005 Jul 1;566(Pt 1):225-36
references.pmid: 15860532
references.citation: Nucleic Acids Res. 2003 May 1;31(9):2305-12
references.pmid: 12711675
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Am J Physiol Cell Physiol. 2006 Feb;290(2):C650-9
references.pmid: 16176969
references.citation: J Biol Chem. 1994 Nov 11;269(45):28514-21
references.pmid: 7545962
references.citation: Annu Rev Nutr. 1994;14:21-40
references.pmid: 7946518
references.citation: Endocrinology. 2013 Jan;154(1):102-13
references.pmid: 23183174
references.citation: Diabetes. 2012 Jun;61(6):1391-8
references.pmid: 22461568
references.citation: PLoS Genet. 2012;8(11):e1003047
references.pmid: 23144632
references.citation: J Biol Chem. 1998 Jun 5;273(23):14285-92
references.pmid: 9603935
references.citation: N Engl J Med. 1994 Sep 29;331(13):847-53
references.pmid: 8078532
references.citation: Science. 2002 Mar 8;295(5561):1901-4
references.pmid: 11884757
references.citation: Pediatr Res. 2007 May;61(5 Pt 2):30R-37R
references.pmid: 17413847
references.citation: Mol Endocrinol. 2012 Dec;26(12):2071-80
references.pmid: 23015752
references.citation: Biochem Biophys Res Commun. 1990 Aug 31;171(1):182-8
references.pmid: 2203344
references.citation: Mol Endocrinol. 1992 Sep;6(9):1468-78
references.pmid: 1331778
references.citation: PLoS Biol. 2007 Apr;5(4):e81
references.pmid: 17373856
references.citation: Endocrinology. 1995 Oct;136(10):4304-14
references.pmid: 7664649
references.citation: Pediatr Res. 2007 May;61(5 Pt 2):1R-4R
references.pmid: 17452883
references.citation: Diabetes. 2002 May;51(5):1499-506
references.pmid: 11978648
references.citation: Endocrinology. 1993 Sep;133(3):965-71
references.pmid: 8396023
references.citation: Am J Physiol Endocrinol Metab. 2001 Nov;281(5):E1101-9
references.pmid: 11595669
references.citation: J Endocrinol. 2013 Feb 25;216(3):389-402
references.pmid: 23287634
references.citation: Mol Cell Endocrinol. 1994 Apr;100(1-2):125-31
references.pmid: 8056146
references.citation: J Diabetes Res. 2013;2013:390534
references.pmid: 23671867
references.citation: Cell. 2007 Feb 23;128(4):669-81
references.pmid: 17320505
references.citation: Endocrinology. 1997 Mar;138(3):1215-23
references.pmid: 9048629
references.citation: Diabetologia. 2005 Mar;48(3):547-52
references.pmid: 15729577
references.citation: J Biol Chem. 1993 Oct 5;268(28):21021-7
references.pmid: 8407939
references.citation: J Mol Biol. 2001 Nov 23;314(2):195-204
references.pmid: 11718554
references.citation: Genes Dev. 2005 Mar 1;19(5):542-52
references.pmid: 15706033
references.citation: Am J Physiol Endocrinol Metab. 2005 May;288(5):E935-47
references.pmid: 15625086
references.citation: Am J Physiol Endocrinol Metab. 2007 Apr;292(4):E1069-78
references.pmid: 17164433
references.citation: Nat Cell Biol. 2004 Jan;6(1):73-7
references.pmid: 14661024
references.citation: Am J Physiol Endocrinol Metab. 2007 May;292(5):E1270-9
references.pmid: 17213472
references.citation: J Biol Chem. 2008 May 16;283(20):13611-26
references.pmid: 18326493
references.citation: Genes Dev. 1992 Mar;6(3):329-44
references.pmid: 1312497
references.citation: Nat Biotechnol. 2004 Aug;22(8):1013-6
references.pmid: 15235610
references.citation: Endocrinology. 2012 Sep;153(9):4216-26
references.pmid: 22807491
references.citation: Eur J Cancer. 2005 Nov;41(16):2381-402
references.pmid: 16226460