diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM2015212-19diaendo-6824Research ArticleВопросы патогенезаPathogenesisМолекулярные и клеточные механизмы адипогенезаMolecular and cellular mechanisms of adipogenesisЕгоровАлександр ДмитриевичEgorovAlexander Dmitrievich

аспирант кафедры биохимии и молекулярной медицины, Факультет фундаментальной медицины МГУ

MD, Research fellow, Department of Biochemistry and Molecular Medicine, Faculty of Fundamental Medicine

egorov.alek@gmail.comПеньковДмитрий НиколаевичPenkovDmitry Nikolaevich

кандидат физико-математических наук, ведущий научный сотрудник лаборатории молекулярной эндокринологии, Институт экспериментальной кардиологии, РКНПК МЗ РФ

PhD in Physics and Mathematics, Leading research associate, Laboratory for Molecular Endocrinology, Institute of Experimental Cardiology

dpenkov@yahoo.comТкачукВсеволод АрсеньевичTkachukVsevolod Arsen'evich

доктор биологических наук, академик, заведующий кафедрой биохимии и молекулярной медицины, Факультет фундаментальной медицины МГУ, заведующий лабораторией молекулярной эндокринологии, Институт экспериментальной кардиологии РКНПК МЗ РФ

PhD in Biology, Academician of Russian Academy of Sciences, Head of Department of Biochemistry and Molecular Medicine in Faculty of Fundamental Medicine (Lomonosov Moscow State University), Head of Laboratory for Molecular Endocrinology in Institute of Experimental Cardiology (Russian Cardiology Research and Production Complex)

tkachuk@fbm.msu.ruГБОУ ВПО Московский государственный университет им. М.В. Ломоносова, МоскваРоссияLomonosov Moscow State University, MoscowRussian FederationФГБУ Российский кардиологический научно-производственный комплекс, МоскваРоссияRussian Cardiology Research and Production Complex, MoscowRussian FederationГБОУ ВПО Московский государственный университет им. М.В. Ломоносова, Москва; ФГБУ Российский кардиологический научно-производственный комплекс, МоскваРоссияLomonosov Moscow State University, MoscowRussian Federation2015030320151821219Copyright © Егоров А.Д., Пеньков Д.Н., Ткачук В.А., 20152015Егоров А.Д., Пеньков Д.Н., Ткачук В.А.Egorov A.D., Penkov D.N., Tkachuk V.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/6824

Ожирение является одной из причин метаболического синдрома, включающего инсулинорезистентность, гипертриглицеридемию и артериальную гипертензию, а также серьезным фактором риска развития сердечно-сосудистых заболеваний. Это обусловлено тем, что жировая ткань ? эндокринный орган, и нарушения ее нормальной функции приводят к системным последствиям. Объем жировой ткани зависит как от размера жировых клеток, так и от их общего количества. Процессом, определяющим количество жировых клеток, является адипогенная дифференцировка. Транскрипционный каскад, регулирующий эту дифференцировку, хорошо изучен. Мастер-регулятором адипогенной дифференцировки является PPAR.?. ? ядерный рецептор, лиганды которого используются в терапии сахарного диабета 2-го типа (СД2) и метаболического синдрома. В статье рассмотрены основные молекулярные и клеточные механизмы адипогенеза, а также влияние на этот процесс инсулина, глюкокортикоидов, цАМФ-активирующих агентов, ядерных рецепторов и факторов транскрипции. Описаны регуляторные области генома, способные связывать множество факторов транскрипции при адипогенной дифференцировке. Обсуждены наиболее перспективные мишени для поиска новых лекарственных препаратов для лечения ожирения и метаболического синдрома, среди которых, наряду сPPAR.?., находится гомеодомен-содержащие белки Pbx1 и Prep1.

The main components of metabolic syndrome include insulin resistance, hypertriglyceridemia and arterial hypertension. Obesity is the cause of metabolic syndrome, mainly as a consequence of the endocrine function of adipose tissue. The volume of adipose tissue depends on the size of individual adipocytes and on their number. The number of adipocytes increases as a result of enhanced adipocyte differentiation. The transcriptional cascade that regulates this differentiation has been well studied. The major adipogenic transcription factor peroxisome proliferator-activated receptor gamma is a ligand-activated nuclear receptor with essential roles in adipogenesis. Its ligands are used to treat metabolic syndrome and type 2 diabetes mellitus. . The present article describes the basic molecular and cellular mechanisms of adipogenesis and discusses the impact of insulin, glucocorticoids, cyclic adenosine monophosphate-activating agents, nuclear receptors and transcription factors on the process of adipogenesis. New regulatory regions of the genome that are capable of binding multiple transcription factors are described, and the most promising drug targets for the treatment of metabolic syndrome and obesity, including the homeodomain proteins Pbx1 and Prep1, are discussed..

адипогенезтранскрипционные факторыактивация транскрипцииPPAR?гомеодоменсодержащие белкиadipogenesistranscription factorstranscriptional activationPPAR?homeodomain proteinsРоссийский Научный Фонд (проект № 14-35-00026)Russian Science Foundation (project #14-35-00026)ВведениеФункции жировой тканиРазвитие адипоцитовЭкспериментальное моделирование адипогенезаТранскрипционные факторы адипогенезаТранскрипционные сети адипогенезаPBX1 и PREP1ЗаключениеReferencesDíez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003;148(3):293-300. doi: 10.1530/eje.0.1480293Díez JJ, Iglesias P. The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 2003;148(3):293-300. doi: 10.1530/eje.0.1480293Denzel MS, Scimia MC, Zumstein PM, et al. T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest. 2010;120(12):4342-4352. doi: 10.1172/JCI43464Denzel MS, Scimia MC, Zumstein PM, et al. T-cadherin is critical for adiponectin-mediated cardioprotection in mice. J Clin Invest. 2010;120(12):4342-4352. doi: 10.1172/JCI43464Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941-946. doi: 10.1038/90984Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941-946. doi: 10.1038/90984Hirsch J, Batchelor B. Adipose tissue cellularity in obesity. Clin Endocrinol Metab. 1976;5(2):299-311. doi: 10.1016/S0300-595X(76)80023-0Hirsch J, Batchelor B. Adipose tissue cellularity in obesity. Clin Endocrinol Metab. 1976;5(2):299-311. doi: 10.1016/S0300-595X(76)80023-0Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006;7(12):885-896. doi: 10.1038/nrm2066Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006;7(12):885-896. doi: 10.1038/nrm2066Birsoy K, Berry R, Wang T, et al. Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis. Development. 2011;138(21):4709-4719. doi: 10.1242/dev.067710Birsoy K, Berry R, Wang T, et al. Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis. Development. 2011;138(21):4709-4719. doi: 10.1242/dev.067710Greenwood MR, Hirsch J. Postnatal development of adipocyte cellularity in the normal rat. J Lipid Res. 1974;15(5):474-483.Greenwood MR, Hirsch J. Postnatal development of adipocyte cellularity in the normal rat. J Lipid Res. 1974;15(5):474-483.Poissonnet CM, Burdi AR, Bookstein FL. Growth and development of human adipose tissue during early gestation. Early Hum Dev. 1983;8(1):1-11. doi: 10.1016/0378-3782(83)90028-2Poissonnet CM, Burdi AR, Bookstein FL. Growth and development of human adipose tissue during early gestation. Early Hum Dev. 1983;8(1):1-11. doi: 10.1016/0378-3782(83)90028-2Poissonnet CM, Burdi AR, Garn SM. The chronology of adipose tissue appearance and distribution in the human fetus. Early Hum Dev. 1984;10(1-2):1-11. doi: 10.1016/0378-3782(84)90106-3Poissonnet CM, Burdi AR, Garn SM. The chronology of adipose tissue appearance and distribution in the human fetus. Early Hum Dev. 1984;10(1-2):1-11. doi: 10.1016/0378-3782(84)90106-3Knittle JL, Timmers K, Ginsberg-Fellner F, et al. The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J Clin Invest. 1979;63(2):239-246. doi: 10.1172/JCI109295Knittle JL, Timmers K, Ginsberg-Fellner F, et al. The growth of adipose tissue in children and adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J Clin Invest. 1979;63(2):239-246. doi: 10.1172/JCI109295Rigamonti A, Brennand K, Lau F, Cowan CA. Rapid cellular turnover in adipose tissue. PLoS One. 2011;6(3):e17637. doi: 10.1371/journal.pone.0017637Rigamonti A, Brennand K, Lau F, Cowan CA. Rapid cellular turnover in adipose tissue. PLoS One. 2011;6(3):e17637. doi: 10.1371/journal.pone.0017637Spalding KL, Arner E, Westermark PO et al. Dynamics of fat cell turnover in humans. Nature. 2008; 453, 783–787. doi: 10.1038/nature06902Spalding KL, Arner E, Westermark PO et al. Dynamics of fat cell turnover in humans. Nature. 2008; 453, 783–787. doi: 10.1038/nature06902Löffler G, Hauner H. Adipose tissue development: the role of precursor cells and adipogenic factors. Part II: The regulation of the adipogenic conversion by hormones and serum factors. KlinWochenschr. 1987 Sep 1; 65(17), 812-817. doi: 10.1007/BF01727475Löffler G, Hauner H. Adipose tissue development: the role of precursor cells and adipogenic factors. Part II: The regulation of the adipogenic conversion by hormones and serum factors. KlinWochenschr. 1987 Sep 1; 65(17), 812-817. doi: 10.1007/BF01727475Géloën A, Roy PE, Bukowiecki LJ. Regression of white adipose tissue in diabetic rats. Am J Physiol. 1989; 257(4 Pt 1):E547-553.Géloën A, Roy PE, Bukowiecki LJ. Regression of white adipose tissue in diabetic rats. Am J Physiol. 1989; 257(4 Pt 1):E547-553.Cawthorn WP, Scheller EL, MacDougald OA. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J Lipid Res. 2012;53(2):227-246. doi: 10.1194/jlr.R021089Cawthorn WP, Scheller EL, MacDougald OA. Adipose tissue stem cells meet preadipocyte commitment: going back to the future. J Lipid Res. 2012;53(2):227-246. doi: 10.1194/jlr.R021089Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. Cell. 2008;135(2):240-249. doi: 10.1016/j.cell.2008.09.036Rodeheffer MS, Birsoy K, Friedman JM. Identification of white adipocyte progenitor cells in vivo. Cell. 2008;135(2):240-249. doi: 10.1016/j.cell.2008.09.036Berry R, Rodeheffer MS. Characterization of the adipocyte cellular lineage in vivo. Nat Cell Biol. 2013;15(3):302-308. doi: 10.1038/ncb2696Berry R, Rodeheffer MS. Characterization of the adipocyte cellular lineage in vivo. Nat Cell Biol. 2013;15(3):302-308. doi: 10.1038/ncb2696Jeffery E, Berry R, Church CD et al. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte. 2014;3(3):206-211. doi: 10.4161/adip.29674Jeffery E, Berry R, Church CD et al. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte. 2014;3(3):206-211. doi: 10.4161/adip.29674Timmons JA, Wennmalm K, Larsson O, et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl AcadSci USA. 2007;104(11):4401-4406. doi: 10.1073/pnas.0610615104Timmons JA, Wennmalm K, Larsson O, et al. Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages. Proc Natl AcadSci USA. 2007;104(11):4401-4406. doi: 10.1073/pnas.0610615104Seale P, Bjork B, Yang W, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454(7207):961-967. doi: 10.1038/nature07182Seale P, Bjork B, Yang W, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;454(7207):961-967. doi: 10.1038/nature07182Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121(1):96-105. doi: 10.1172/JCI44271Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, Cohen P, Cinti S, Spiegelman BM. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest. 2011;121(1):96-105. doi: 10.1172/JCI44271Green H, Kehinde O. An established preadipose cell line and its differentiation in culture. Cell. 1974;1:113–116. doi: 10.1016/0092-8674(74)90126-3Green H, Kehinde O. An established preadipose cell line and its differentiation in culture. Cell. 1974;1:113–116. doi: 10.1016/0092-8674(74)90126-3Novikoff AB, Novikoff PM, Rosen OM, et al. Organelle relationships in cultured 3T3-L1 preadipocytes. J Cell Biol. 1980;87(1):180-196. doi: 10.1083/jcb.87.1.180Novikoff AB, Novikoff PM, Rosen OM, et al. Organelle relationships in cultured 3T3-L1 preadipocytes. J Cell Biol. 1980;87(1):180-196. doi: 10.1083/jcb.87.1.180Green H, Kehinde O. Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. J Cell Physiol. 1979;101:169–172. doi: 10.1002/jcp.1041010119Green H, Kehinde O. Formation of normally differentiated subcutaneous fat pads by an established preadipose cell line. J Cell Physiol. 1979;101:169–172. doi: 10.1002/jcp.1041010119Student AK, Hsu RY, Lane MD. Induction of fatty acid synthetase synthesis indifferentiating 3T3-L1 preadipocytes. J Biol Chem. 1980;255(10):4745-4750.Student AK, Hsu RY, Lane MD. Induction of fatty acid synthetase synthesis indifferentiating 3T3-L1 preadipocytes. J Biol Chem. 1980;255(10):4745-4750.Smith PJ, Wise LS, Berkowitz R, et al. Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes. J Biol Chem. 1988;263(19):9402-9408.Smith PJ, Wise LS, Berkowitz R, et al. Insulin-like growth factor-I is an essential regulator of the differentiation of 3T3-L1 adipocytes. J Biol Chem. 1988;263(19):9402-9408.Scott RE, Florine DL, Wille JJ Jr, et al. Coupling of growth arrest and differentiation at a distinct state in the G1 phase of the cell cycle: GD. Proc Natl AcadSci USA. 1982;79(3):845-849. doi: 10.1073/pnas.79.3.845Scott RE, Florine DL, Wille JJ Jr, et al. Coupling of growth arrest and differentiation at a distinct state in the G1 phase of the cell cycle: GD. Proc Natl AcadSci USA. 1982;79(3):845-849. doi: 10.1073/pnas.79.3.845Cornelius P, MacDougald OA, Lane MD. Regulation of adipocyte development. Annu Rev Nutr. 1994;14:99-129. doi: 10.1146/annurev.nu.14.070194.000531Cornelius P, MacDougald OA, Lane MD. Regulation of adipocyte development. Annu Rev Nutr. 1994;14:99-129. doi: 10.1146/annurev.nu.14.070194.000531MacDougald OA, Lane MD. Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem. 1995;64:345-373. doi: 10.1146/annurev.bi.64.070195.002021MacDougald OA, Lane MD. Transcriptional regulation of gene expression during adipocyte differentiation. Annu Rev Biochem. 1995;64:345-373. doi: 10.1146/annurev.bi.64.070195.002021Siersbæk R, Nielsen R, Mandrup S. Transcriptional networks and chromatin remodeling controlling adipogenesis. Trends Endocrinol Metab. 2012;23(2):56-64. doi: 10.1016/j.tem.2011.10.001Siersbæk R, Nielsen R, Mandrup S. Transcriptional networks and chromatin remodeling controlling adipogenesis. Trends Endocrinol Metab. 2012;23(2):56-64. doi: 10.1016/j.tem.2011.10.001Tanaka T, Yoshida N, Kishimoto T, et al. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 1997;16(24):7432-7443. doi: 10.1093/emboj/16.24.7432Tanaka T, Yoshida N, Kishimoto T, et al. Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J. 1997;16(24):7432-7443. doi: 10.1093/emboj/16.24.7432Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991;5(9):1538-1552. doi: 10.1101/gad.5.9.1538Cao Z, Umek RM, McKnight SL. Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev. 1991;5(9):1538-1552. doi: 10.1101/gad.5.9.1538Yeh WC, Cao Z, Classon M, et al. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 1995;9(2):168-181. doi: 10.1101/gad.9.2.168Yeh WC, Cao Z, Classon M, et al. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 1995;9(2):168-181. doi: 10.1101/gad.9.2.168Hamm JK, Park BH, Farmer SR. A role for C/EBPbeta in regulating peroxisome proliferator-activated receptor gamma activity during adipogenesis in 3T3-L1 preadipocytes. J Biol Chem. 2001;276(21):18464-18471. doi: 10.1074/jbc.M100797200Hamm JK, Park BH, Farmer SR. A role for C/EBPbeta in regulating peroxisome proliferator-activated receptor gamma activity during adipogenesis in 3T3-L1 preadipocytes. J Biol Chem. 2001;276(21):18464-18471. doi: 10.1074/jbc.M100797200Christy RJ, Kaestner KH, Geiman DE, et al. CCAAT/enhancer binding protein gene promoter: binding of nuclear factors during differentiation of 3T3-L1 preadipocytes. Proc Natl AcadSci USA. 1991;88(6):2593-2597. doi: 10.1073/pnas.88.6.2593Christy RJ, Kaestner KH, Geiman DE, et al. CCAAT/enhancer binding protein gene promoter: binding of nuclear factors during differentiation of 3T3-L1 preadipocytes. Proc Natl AcadSci USA. 1991;88(6):2593-2597. doi: 10.1073/pnas.88.6.2593Zhang JW, Klemm DJ, Vinson C, et al. Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis. J Biol Chem. 2004;279(6):4471-4478. doi: 10.1074/jbc.M311327200Zhang JW, Klemm DJ, Vinson C, et al. Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis. J Biol Chem. 2004;279(6):4471-4478. doi: 10.1074/jbc.M311327200Blüher M, Michael MD, Peroni OD, et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002;3(1):25-38. doi: 10.1016/S1534-5807(02)00199-5Blüher M, Michael MD, Peroni OD, et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002;3(1):25-38. doi: 10.1016/S1534-5807(02)00199-5Tseng YH, Kriauciunas KM, Kokkotou E, et al. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol Cell Biol. 2004;24(5):1918-1929. doi: 10.1128/MCB.24.5.1918-1929.2004Tseng YH, Kriauciunas KM, Kokkotou E, et al. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol Cell Biol. 2004;24(5):1918-1929. doi: 10.1128/MCB.24.5.1918-1929.2004Miki H, Yamauchi T, Suzuki R, et al. Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Mol Cell Biol. 2001;21(7):2521-2532. doi: 10.1128/MCB.21.7.2521-2532.2001Miki H, Yamauchi T, Suzuki R, et al. Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Mol Cell Biol. 2001;21(7):2521-2532. doi: 10.1128/MCB.21.7.2521-2532.2001Garofalo RS, Orena SJ, Rafidi K, et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest. 2003;112(2):197-208. doi: 10.1172/JCI16885Garofalo RS, Orena SJ, Rafidi K, et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest. 2003;112(2):197-208. doi: 10.1172/JCI16885George S, Rochford JJ, Wolfrum C, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304(5675):1325-1328. doi: 10.1126/science.1096706George S, Rochford JJ, Wolfrum C, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304(5675):1325-1328. doi: 10.1126/science.1096706Wolfrum C, Shih DQ, Kuwajima S, et al. Role of Foxa-2 in adipocyte metabolism and differentiation. J Clin Invest. 2003;112(3):345-356. doi: 10.1172/JCI18698Wolfrum C, Shih DQ, Kuwajima S, et al. Role of Foxa-2 in adipocyte metabolism and differentiation. J Clin Invest. 2003;112(3):345-356. doi: 10.1172/JCI18698Nakae J, Kitamura T, Kitamura Y, et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell. 2003;4(1):119-129. doi: 10.1016/S1534-5807(02)00401-XNakae J, Kitamura T, Kitamura Y, et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev Cell. 2003;4(1):119-129. doi: 10.1016/S1534-5807(02)00401-XKim JB, Wright HM, Wright M, et al. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proc Natl AcadSci USA. 1998;95(8):4333-4337. doi: 10.1073/pnas.95.8.4333Kim JB, Wright HM, Wright M, et al. ADD1/SREBP1 activates PPARgamma through the production of endogenous ligand. Proc Natl AcadSci USA. 1998;95(8):4333-4337. doi: 10.1073/pnas.95.8.4333Pantoja C, Huff JT, Yamamoto KR. Glucocorticoid signaling defines a novel commitment state during adipogenesis in vitro. Mol Cell Biol. 2008;19(10):4032-4041. doi: 10.1091/mbc.e08-04-0420Pantoja C, Huff JT, Yamamoto KR. Glucocorticoid signaling defines a novel commitment state during adipogenesis in vitro. Mol Cell Biol. 2008;19(10):4032-4041. doi: 10.1091/mbc.e08-04-0420Linhart HG, Ishimura-Oka K, DeMayo F, et al. C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proc Natl AcadSci USA. 2001;98(22):12532-12537. doi: 10.1073/pnas.211416898Linhart HG, Ishimura-Oka K, DeMayo F, et al. C/EBPalpha is required for differentiation of white, but not brown, adipose tissue. Proc Natl AcadSci USA. 2001;98(22):12532-12537. doi: 10.1073/pnas.211416898Lefterova MI, Zhang Y, Steger DJ, et al. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 2008;22(21):2941-2952. doi: 10.1101/gad.1709008Lefterova MI, Zhang Y, Steger DJ, et al. PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 2008;22(21):2941-2952. doi: 10.1101/gad.1709008Madsen MS, Siersbæk R, Boergesen M, et al. Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading. Mol Cell Biol. 2014;34(6):939-954. doi: 10.1128/MCB.01344-13Madsen MS, Siersbæk R, Boergesen M, et al. Peroxisome proliferator-activated receptor γ and C/EBPα synergistically activate key metabolic adipocyte genes by assisted loading. Mol Cell Biol. 2014;34(6):939-954. doi: 10.1128/MCB.01344-13Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992;358(6389):771-774. doi: 10.1038/358771a0Kliewer SA, Umesono K, Noonan DJ, et al. Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature. 1992;358(6389):771-774. doi: 10.1038/358771a0Lehmann JM, Lenhard JM, Oliver BB, et al. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997;272(6):3406-3410. doi: 10.1074/jbc.272.6.3406Lehmann JM, Lenhard JM, Oliver BB, et al. Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997;272(6):3406-3410. doi: 10.1074/jbc.272.6.3406Siersbæk R, Rabiee A, Nielsen R, et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 2014;7(5):1443-1455. doi: 10.1016/j.celrep.2014.04.042Siersbæk R, Rabiee A, Nielsen R, et al. Transcription factor cooperativity in early adipogenic hotspots and super-enhancers. Cell Rep. 2014;7(5):1443-1455. doi: 10.1016/j.celrep.2014.04.042Monteiro MC, Sanyal M, Cleary ML, et al. PBX1: a novel stage-specific regulator of adipocyte development. Stem Cells. 2011;29(11):1837-1848. doi: 10.1002/stem.737Monteiro MC, Sanyal M, Cleary ML, et al. PBX1: a novel stage-specific regulator of adipocyte development. Stem Cells. 2011;29(11):1837-1848. doi: 10.1002/stem.737Berthelsen J, Zappavigna V, Mavilio F, et al. Prep1, a novel functional partner of Pbx proteins. EMBO J. 1998;17(5):1423-1433. doi: 10.1093/emboj/17.5.1423Berthelsen J, Zappavigna V, Mavilio F, et al. Prep1, a novel functional partner of Pbx proteins. EMBO J. 1998;17(5):1423-1433. doi: 10.1093/emboj/17.5.1423Ferretti E, Cambronero F, Tümpel S, et al. Hoxb1 enhancer and control of rhombomere 4 expression: complex interplay between PREP1-PBX1-HOXB1 binding sites. Mol Cell Biol. 2005;25(19):8541-8552. doi: 10.1128/MCB.25.19.8541-8552.2005Ferretti E, Cambronero F, Tümpel S, et al. Hoxb1 enhancer and control of rhombomere 4 expression: complex interplay between PREP1-PBX1-HOXB1 binding sites. Mol Cell Biol. 2005;25(19):8541-8552. doi: 10.1128/MCB.25.19.8541-8552.2005Selleri L, Depew MJ, Jacobs Y, et al. Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development. 2001;128(18):3543-3557.Selleri L, Depew MJ, Jacobs Y, et al. Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development. 2001;128(18):3543-3557.Fernandez-Diaz LC, Laurent A, Girasoli S, et al. The absence of Prep1 causes p53-dependent apoptosis of mouse pluripotent epiblast cells. Development. 2010;137(20):3393-3403. doi: 10.1242/dev.050567Fernandez-Diaz LC, Laurent A, Girasoli S, et al. The absence of Prep1 causes p53-dependent apoptosis of mouse pluripotent epiblast cells. Development. 2010;137(20):3393-3403. doi: 10.1242/dev.050567

The authors declare that there are no conflicts of interest present.