Reduced SIRT1 and SIRT2 expression promotes adipogenesis of human visceral adipose stem cells and associates with accumulation of visceral fat in human obesity.
Journal
International journal of obesity (2005)
ISSN: 1476-5497
Titre abrégé: Int J Obes (Lond)
Pays: England
ID NLM: 101256108
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
20
01
2019
accepted:
08
07
2019
revised:
17
04
2019
pubmed:
30
8
2019
medline:
27
2
2021
entrez:
30
8
2019
Statut:
ppublish
Résumé
The histone deacetylases SIRT1 and SIRT2 have been shown to be involved in the differentiation of rodent adipocyte precursors. In light of the differences in gene expression and metabolic function of visceral (V) and subcutaneous (S) adipose tissue (AT) and their resident cells, the aim of this study was to investigate the role of SIRT1 and SIRT2 in the differentiation of adipose stem cells (ASCs) isolated from SAT and VAT biopsies of nondiabetic obese and nonobese individuals. Human ASCs were isolated from paired SAT and VAT biopsies obtained from 83 nonobese and 92 obese subjects and were differentiated in vitro. Adipogenesis was evaluated by analyzing the lipid deposition using an image processing software, and gene expression by RT-qPCR. SIRT1 and SIRT2 protein expression was modified by using recombinant adenoviral vectors. Visceral but not subcutaneous ASCs from obese subjects showed an intrinsic increase in both adipogenesis and lipid accumulation when compared with ASCs from nonobese subjects, and this was associated with reduced SIRT1 and SIRT2 mRNA and protein levels. Moreover, adipose tissue mRNA levels of SIRT1 and SIRT2 showed an inverse correlation with BMI in the visceral but not subcutaneous depot. Overexpression of SIRT1 or SIRT2 in visceral ASCs from obese subjects resulted in inhibition of adipocyte differentiation, whereas knockdown of SIRT1 or SIRT2 in visceral ASCs from nonobese subjects enhanced this process. Changes in SIRT1 or SIRT2 expression and adipocyte differentiation were paralleled by corresponding changes in PPARG, CEBPA, and other genes marking terminal adipocyte differentiation. SIRT1 and SIRT2 modulate the differentiation of human ASC. Reduced expression of SIRT1 and SIRT2 may enhance the differentiation capacity of visceral ASC in human obesity, fostering visceral adipose tissue expansion.
Sections du résumé
BACKGROUND/OBJECTIVES
The histone deacetylases SIRT1 and SIRT2 have been shown to be involved in the differentiation of rodent adipocyte precursors. In light of the differences in gene expression and metabolic function of visceral (V) and subcutaneous (S) adipose tissue (AT) and their resident cells, the aim of this study was to investigate the role of SIRT1 and SIRT2 in the differentiation of adipose stem cells (ASCs) isolated from SAT and VAT biopsies of nondiabetic obese and nonobese individuals.
METHODS
Human ASCs were isolated from paired SAT and VAT biopsies obtained from 83 nonobese and 92 obese subjects and were differentiated in vitro. Adipogenesis was evaluated by analyzing the lipid deposition using an image processing software, and gene expression by RT-qPCR. SIRT1 and SIRT2 protein expression was modified by using recombinant adenoviral vectors.
RESULTS
Visceral but not subcutaneous ASCs from obese subjects showed an intrinsic increase in both adipogenesis and lipid accumulation when compared with ASCs from nonobese subjects, and this was associated with reduced SIRT1 and SIRT2 mRNA and protein levels. Moreover, adipose tissue mRNA levels of SIRT1 and SIRT2 showed an inverse correlation with BMI in the visceral but not subcutaneous depot. Overexpression of SIRT1 or SIRT2 in visceral ASCs from obese subjects resulted in inhibition of adipocyte differentiation, whereas knockdown of SIRT1 or SIRT2 in visceral ASCs from nonobese subjects enhanced this process. Changes in SIRT1 or SIRT2 expression and adipocyte differentiation were paralleled by corresponding changes in PPARG, CEBPA, and other genes marking terminal adipocyte differentiation.
CONCLUSIONS
SIRT1 and SIRT2 modulate the differentiation of human ASC. Reduced expression of SIRT1 and SIRT2 may enhance the differentiation capacity of visceral ASC in human obesity, fostering visceral adipose tissue expansion.
Identifiants
pubmed: 31462690
doi: 10.1038/s41366-019-0436-7
pii: 10.1038/s41366-019-0436-7
doi:
Substances chimiques
SIRT1 protein, human
EC 3.5.1.-
SIRT2 protein, human
EC 3.5.1.-
Sirtuin 1
EC 3.5.1.-
Sirtuin 2
EC 3.5.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
307-319Références
Lindroos J, Husa J, Mitterer G, Haschemi A, Rauscher S, Haas R, et al. Human but not mouse adipogenesis is critically dependent on LMO3. Cell Metab. 2013;18:62–74.
doi: 10.1016/j.cmet.2013.05.020
pubmed: 23823477
pmcid: 3701325
Tran TT, Kahn CR. Transplantation of adipose tissue and stem cells: role in metabolism and disease. Nat Rev Endocrinol. 2010;6:195–213.
doi: 10.1038/nrendo.2010.20
pubmed: 20195269
pmcid: 4362513
Laviola L, Perrini S, Cignarelli A, Natalicchio A, Leonardini A, De Stefano F, et al. Insulin signaling in human visceral and subcutaneous adipose tissue in vivo. Diabetes. 2006;55:952–61.
doi: 10.2337/diabetes.55.04.06.db05-1414
pubmed: 16567516
Perrini S, Laviola L, Cignarelli A, Melchiorre M, De Stefano F, Caccioppoli C, et al. Fat depot-related differences in gene expression, adiponectin secretion, and insulin action and signalling in human adipocytes differentiated in vitro from precursor stromal cells. Diabetologia. 2008;51:155–64.
doi: 10.1007/s00125-007-0841-7
pubmed: 17960360
Perrini S, Ficarella R, Picardi E, Cignarelli A, Barbaro M, Nigro P, et al. Differences in gene expression and cytokine release profiles highlight the heterogeneity of distinct subsets of adipose tissue-derived stem cells in the subcutaneous and visceral adipose tissue in humans. PLoS ONE. 2013;8:e57892.
doi: 10.1371/journal.pone.0057892
pubmed: 23526958
pmcid: 3589487
Macotela Y, Emanuelli B, Mori MA, Gesta S, Schulz TJ, Tseng Y-H, et al. Intrinsic differences in adipocyte precursor cells from different white fat depots. Diabetes. 2012;61:1691–9.
doi: 10.2337/db11-1753
pubmed: 22596050
pmcid: 3379665
Tchkonia T, Thomou T, Zhu Y, Karagiannides I, Pothoulakis C, Jensen MD, et al. Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 2013;17:644–56.
doi: 10.1016/j.cmet.2013.03.008
pubmed: 23583168
pmcid: 3942783
Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, et al. Dynamics of fat cell turnover in humans. Nature. 2008;453:783–7.
doi: 10.1038/nature06902
pubmed: 18454136
pmcid: 18454136
Arner E, Westermark PO, Spalding KL, Britton T, Rydén M, Frisén J, et al. Adipocyte turnover: relevance to human adipose tissue morphology. Diabetes. 2010;59:105–9.
doi: 10.2337/db09-0942
pubmed: 19846802
Gomes P, Fleming Outeiro T, Cavadas C. Emerging role of sirtuin 2 in the regulation of mammalian metabolism. Trends Pharmacol Sci. 2015;36:756–68.
doi: 10.1016/j.tips.2015.08.001
pubmed: 26538315
Chang H-C, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25:138–45.
doi: 10.1016/j.tem.2013.12.001
pubmed: 24388149
Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado de Oliveira R, et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature. 2004;429:771–6.
doi: 10.1038/nature02583
pubmed: 15175761
pmcid: 2820247
Jing E, Gesta S, Kahn CR. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 2007;6:105–14.
doi: 10.1016/j.cmet.2007.07.003
pubmed: 17681146
pmcid: 2083635
Mayoral R, Osborn O, McNelis J, Johnson AM, Oh DY, Izquierdo CL, et al. Adipocyte SIRT1 knockout promotes PPARγ activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol Metab. 2015;4:378–91.
doi: 10.1016/j.molmet.2015.02.007
pubmed: 25973386
pmcid: 4421024
Bordone L, Cohen D, Robinson A, Motta MC, van Veen E, Czopik A, et al. SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell. 2007;6:759–67.
doi: 10.1111/j.1474-9726.2007.00335.x
pubmed: 17877786
Kurylowicz A, Owczarz M, Polosak J, Jonas MI, Lisik W, Jonas M, et al. SIRT1 and SIRT7 expression in adipose tissues of obese and normal-weight individuals is regulated by microRNAs but not by methylation status. Int J Obes. 2016;40:1635–42.
doi: 10.1038/ijo.2016.131
Martínez-Jiménez V, Cortez-Espinosa N, Rodríguez-Varela E, Vega-Cárdenas M, Briones-Espinoza M, Ruíz-Rodríguez VM, et al. Altered levels of sirtuin genes (SIRT1, SIRT2, SIRT3 and SIRT6) and their target genes in adipose tissue from individual with obesity. Diabetes Metab Syndr. 2019;13:582–9.
doi: 10.1016/j.dsx.2018.11.011
pubmed: 30641770
Cignarelli A, Melchiorre M, Peschechera A, Conserva A, Renna LA, Miccoli S, et al. Role of UBC9 in the regulation of the adipogenic program in 3T3-L1 adipocytes. Endocrinology. 2010;151:5255–66.
doi: 10.1210/en.2010-0417
pubmed: 20881252
Cignarelli A, Perrini S, Nigro P, Ficarella R, Barbaro M, Peschechera A, et al. Long-acting insulin analog detemir displays reduced effects on adipocyte differentiation of human subcutaneous and visceral adipose stem cells. Nutr Metab Cardiovasc Dis. 2016;26:333–44.
doi: 10.1016/j.numecd.2015.11.010
pubmed: 26947594
Lee KY, Gesta S, Boucher J, Wang XL, Kahn CR. The differential role of Hif1β/Arnt and the hypoxic response in adipose function, fibrosis, and inflammation. Cell Metab. 2011;14:491–503.
doi: 10.1016/j.cmet.2011.08.006
pubmed: 21982709
pmcid: 3206000
Perrini S, Cignarelli A, Quaranta VN, Falcone VA, Kounaki S, Porro S, et al. Correction of intermittent hypoxia reduces inflammation in obese subjects with obstructive sleep apnea. JCI Insight. 2017;2. pii: 94379.
Perrini S, Tortosa F, Natalicchio A, Pacelli C, Cignarelli A, Palmieri VO, et al. The p66
doi: 10.1152/ajpgi.00041.2015
pubmed: 26336926
Moschen AR, Wieser V, Gerner RR, Bichler A, Enrich B, Moser P, et al. Adipose tissue and liver expression of SIRT1, 3, and 6 increase after extensive weight loss in morbid obesity. J Hepatol. 2013;59:1315–22.
doi: 10.1016/j.jhep.2013.07.027
pubmed: 23928404
Pedersen SB, Ølholm J, Paulsen SK, Bennetzen MF, Richelsen B. Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women. Int J Obes. 2008;32:1250–5.
doi: 10.1038/ijo.2008.78
Song YS, Lee SK, Jang YJ, Park HS, Kim J-H, Lee YJ, et al. Association between low SIRT1 expression in visceral and subcutaneous adipose tissues and metabolic abnormalities in women with obesity and type 2 diabetes. Diabetes Res Clin Pract. 2013;101:341–8.
doi: 10.1016/j.diabres.2013.07.002
pubmed: 23876548
Jukarainen S, Heinonen S, Rämö JT, Rinnankoski-Tuikka R, Rappou E, Tummers M, et al. Obesity is associated with low NAD+/SIRT pathway expression in adipose tissue of BMI-discordant monozygotic twins. J Clin Endocrinol Metab. 2016;101:275–83.
doi: 10.1210/jc.2015-3095
pubmed: 26574954
Krishnan J, Danzer C, Simka T, Ukropec J, Walter KM, Kumpf S, et al. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev. 2012;26:259–70.
doi: 10.1101/gad.180406.111
pubmed: 22302938
pmcid: 3278893
Lemos V, de Oliveira RM, Naia L, Szegö É, Ramos E, Pinho S, et al. The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes. Hum Mol Genet. 2017;26:4105–17.
doi: 10.1093/hmg/ddx298
pubmed: 28973648
Tchkonia T, Giorgadze N, Pirtskhalava T, Tchoukalova Y, Karagiannides I, Forse RA, et al. Fat depot origin affects adipogenesis in primary cultured and cloned human preadipocytes. Am J Physiol Regul Integr Comp Physiol. 2002;282:R1286–96.
doi: 10.1152/ajpregu.00653.2001
pubmed: 11959668
Baglioni S, Cantini G, Poli G, Francalanci M, Squecco R, Di Franco A, et al. Functional differences in visceral and subcutaneous fat pads originate from differences in the adipose stem cell. PLoS ONE. 2012;7:e36569.
doi: 10.1371/journal.pone.0036569
pubmed: 22574183
pmcid: 3344924
Permana PA, Nair S, Lee Y-H, Luczy-Bachman G, Vozarova de Courten B, Tataranni PA. Subcutaneous abdominal preadipocyte differentiation in vitro inversely correlates with central obesity. Am J Physiol Metab. 2004;286:E958–62.
Isakson P, Hammarstedt A, Gustafson B, Smith U. Impaired preadipocyte differentiation in human abdominal obesity: role of wnt, tumor necrosis factor-alpha, and inflammation. Diabetes. 2009;58:1550–7.
doi: 10.2337/db08-1770
pubmed: 19351711
pmcid: 2699851
Landgraf K, Rockstroh D, Wagner IV, Weise S, Tauscher R, Schwartze JT, et al. Evidence of early alterations in adipose tissue biology and function and its association with obesity-related inflammation and insulin resistance in children. Diabetes. 2015;64:1249–61.
doi: 10.2337/db14-0744
pubmed: 25392242
Gustafson B, Gogg S, Hedjazifar S, Jenndahl L, Hammarstedt A, Smith U. Inflammation and impaired adipogenesis in hypertrophic obesity in man. Am J Physiol Metab. 2009;297:E999–1003.
Kursawe R, Dixit VD, Scherer PE, Santoro N, Narayan D, Gordillo R, et al. A Role of the inflammasome in the low storage capacity of the abdominal subcutaneous adipose tissue in obese adolescents. Diabetes. 2016;65:610–8.
doi: 10.2337/db15-1478
pubmed: 26718495
Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med. 2013;19:1338–44.
doi: 10.1038/nm.3324
pubmed: 23995282
pmcid: 4075943
Mendes KL, Lelis DF, Santos SHS. Nuclear sirtuins and inflammatory signaling pathways. Cytokine Growth Factor Rev. 2017;38:98–105.
doi: 10.1016/j.cytogfr.2017.11.001
pubmed: 29132743
Li P, Zhao Y, Wu X, Xia M, Fang M, Iwasaki Y, et al. Interferon gamma (IFN-γ) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription. Nucleic Acids Res. 2012;40:1609–20.
doi: 10.1093/nar/gkr984
pubmed: 22064865
Lin J, Sun B, Jiang C, Hong H, Zheng Y. Sirt2 suppresses inflammatory responses in collagen-induced arthritis. Biochem Biophys Res Commun. 2013;441:897–903.
doi: 10.1016/j.bbrc.2013.10.153
pubmed: 24211200
Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol. 2008;28:188–200.
doi: 10.1128/MCB.00992-07
pubmed: 17954559
Armoni M, Harel C, Karni S, Chen H, Bar-Yoseph F, Ver MR, et al. FOXO1 represses peroxisome proliferator-activated receptor-γ1 and -γ2 gene promoters in primary adipocytes. J Biol Chem. 2006;281:19881–91.
doi: 10.1074/jbc.M600320200
pubmed: 16670091
Guo L, Li X, Tang Q-Q. Transcriptional regulation of adipocyte differentiation: a central role for CCAAT/enhancer-binding protein (C/EBP) β. J Biol Chem. 2015;290:755–61.
doi: 10.1074/jbc.R114.619957
pubmed: 25451943
Tanaka T, Yoshida N, Kishimoto T, Akira S. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 1997;16:7432–43.
doi: 10.1093/emboj/16.24.7432
pubmed: 9405372
pmcid: 1170343
Takada I, Kouzmenko AP, Kato S. Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol. 2009;5:442–7.
doi: 10.1038/nrrheum.2009.137
pubmed: 19581903
Visweswaran M, Schiefer L, Arfuso F, Dilley RJ, Newsholme P, Dharmarajan A. Wnt antagonist secreted frizzled-related protein 4 upregulates adipogenic differentiation in human adipose tissue-derived mesenchymal stem cells. PLoS ONE. 2015;10:e0118005.
doi: 10.1371/journal.pone.0118005
pubmed: 25714610
pmcid: 4340908
Ehrlund A, Mejhert N, Lorente-Cebrián S, Aström G, Dahlman I, Laurencikiene J, et al. Characterization of the Wnt inhibitors secreted frizzled-related proteins (SFRPs) in human adipose tissue. J Clin Endocrinol Metab. 2013;98:E503–8.
doi: 10.1210/jc.2012-3416
pubmed: 23393180
Guan H, Zhang Y, Gao S, Bai L, Zhao S, Cheng XW, et al. Differential patterns of secreted frizzled-related protein 4 (SFRP4) in adipocyte differentiation: adipose depot specificity. Cell Physiol Biochem. 2018;46:2149–64.
doi: 10.1159/000489545
pubmed: 29730658
Zhou Y, Song T, Peng J, Zhou Z, Wei H, Zhou R, et al. SIRT1 suppresses adipogenesis by activating Wnt/β-catenin signaling in vivo and in vitro. Oncotarget. 2016;7:77707–20.
pubmed: 27776347
pmcid: 5363615