Retinoids and nuclear retinoid receptors in white and brown adipose tissues: physiopathologic aspects

References

1. Farmer SR. Molecular determinants of brown adipocyte formation and function. Genes Dev 2008;22:1269–75.10.1101/gad.1681308Search in Google Scholar PubMed PubMed Central

2. Mattson MP. Perspective: does brown fat protect against diseases of aging? Ageing Res Rev 2010;9:69–76.10.1016/j.arr.2009.11.004Search in Google Scholar PubMed PubMed Central

3. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444–52.10.1152/ajpendo.00691.2006Search in Google Scholar PubMed

4. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. New Engl J Med 2009;360:1509–17.10.1056/NEJMoa0810780Search in Google Scholar PubMed PubMed Central

5. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in healthy men. New Engl J Med 2009;360:1500–8.10.1056/NEJMoa0808718Search in Google Scholar PubMed

6. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto NJ, Enerback S, Nuutila P. Functional brown adipose tissue in healthy adults. New Engl J Med 2009;360:1518–25.10.1056/NEJMoa0808949Search in Google Scholar PubMed

7. Ravussin E, Kozak LP. Have we entered the brown adipose tissue renaissance? Obes Rev 2009;10:265–8.10.1111/j.1467-789X.2008.00559.xSearch in Google Scholar PubMed PubMed Central

8. Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, Nedergaard J, Cinti S. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J 2009;23:3113–20.10.1096/fj.09-133546Search in Google Scholar PubMed

9. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, Scime A, Devarakonda S, Conroe HM, Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008;454:961–7.10.1038/nature07182Search in Google Scholar PubMed PubMed Central

10. Sharp LZ, Shinoda K, Ohno H, Scheel DW, Tomoda E, Ruiz L, Hu H, Wang L, Pavlova Z, Gilsanz V, Kajimura S. Human bat possesses molecular signatures that resemble beige/brite cells. PloS One 2012;7:e49452.10.1371/journal.pone.0049452Search in Google Scholar PubMed PubMed Central

11. Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006;444:847–53.10.1038/nature05483Search in Google Scholar

12. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Ann Rev Nut 2007;27:79–101.10.1146/annurev.nutr.27.061406.093734Search in Google Scholar

13. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab 2004;89:2548–56.10.1210/jc.2004-0395Search in Google Scholar

14. Trayhurn P. Endocrine and signalling role of adipose tissue: new perspectives on fat. Acta Physiol Scand 2005;184:285–93.10.1111/j.1365-201X.2005.01468.xSearch in Google Scholar

15. Bonet ML, Ribot J, Felipe F, Palou A. Vitamin A and the regulation of fat reserves. Cell Mol Life Sci 2003;60:1311–21.10.1007/s00018-003-2290-xSearch in Google Scholar

16. Davis EM. The necessity of certain lipins in the diet during growth. Nutr Rev 1973;31:280–1.Search in Google Scholar

17. Napoli JL. Retinoic acid biosynthesis and metabolism. FASEB J 1996;10:993–1001.10.1096/fasebj.10.9.8801182Search in Google Scholar

18. Harrison EH. Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin a carotenoids. Biochim Biophys Acta 2012;1821:70–7.10.1016/j.bbalip.2011.06.002Search in Google Scholar

19. Soprano DR, Gyda M, 3rd, Jiang H, Harnish DC, Ugen K, Satre M, Chen L, Soprano KJ, Kochhar DM. A sustained elevation in retinoic acid receptor-beta 2 mRNA and protein occurs during retinoic acid-induced fetal dysmorphogenesis. Mech Dev 1994;45:243–53.10.1016/0925-4773(94)90011-6Search in Google Scholar

20. Zanotti G, Berni R. Plasma retinol-binding protein: structure and interactions with retinol, retinoids, and transthyretin. Vitam Horm 2004;69:271–95.10.1016/S0083-6729(04)69010-8Search in Google Scholar

21. Blomhoff R, Green MH, Berg T, Norum KR. Transport and storage of vitamin A. Science 1990;250:399–404.10.1126/science.2218545Search in Google Scholar PubMed

22. Tsutsumi C, Okuno M, Tannous L, Piantedosi R, Allan M, Goodman DS, Blaner WS. Retinoids and retinoid-binding protein expression in rat adipocytes. J Biol Chem 1992;267:1805–10.10.1016/S0021-9258(18)46017-6Search in Google Scholar

23. D’Ambrosio DN, Clugston RD, Blaner WS. Vitamin A metabolism: an update. Nutrients 2011;3:63–103.10.3390/nu3010063Search in Google Scholar

24. Villarroya F, Giralt M, Iglesias R. Retinoids and adipose tissues: metabolism, cell differentiation and gene expression. Int J Obes Relat Metab Disord 1999;23:1–6.10.1038/sj.ijo.0800799Search in Google Scholar

25. van Bennekum AM, Kako Y, Weinstock PH, Harrison EH, Deckelbaum RJ, Goldberg IJ, Blaner WS. Lipoprotein lipase expression level influences tissue clearance of chylomicron retinyl ester. J Lipid Res 1999;40:565–74.10.1016/S0022-2275(20)32461-5Search in Google Scholar

26. Hessel S, Eichinger A, Isken A, Amengual J, Hunzelmann S, Hoeller U, Elste V, Hunziker W, Goralczyk R, Oberhauser V, von Lintig J, Wyss A. Cmo1 deficiency abolishes vitamin a production from beta-carotene and alters lipid metabolism in mice. J Biol Chem 2007;282:33553–61.10.1074/jbc.M706763200Search in Google Scholar

27. Lobo GP, Amengual J, Li HN, Golczak M, Bonet ML, Palczewski K, von Lintig J. Beta,beta-carotene decreases peroxisome proliferator receptor gamma activity and reduces lipid storage capacity of adipocytes in a beta,beta-carotene oxygenase 1-dependent manner. J Biol Chem 2010;285:27891–9.10.1074/jbc.M110.132571Search in Google Scholar

28. Randolph RK, Winkler KE, Ross AC. Fatty acyl CoA-dependent and -independent retinol esterification by rat liver and lactating mammary gland microsomes. Arch Biochem Biophys 1991;288:500–8.10.1016/0003-9861(91)90227-ASearch in Google Scholar

29. Ross AC, Kempner ES. Radiation inactivation analysis of acyl-coA:retinol acyltransferase and lecithin:retinol acyltransferase in rat liver. J Lipid Res 1993;34:1201–7.10.1016/S0022-2275(20)37707-5Search in Google Scholar

30. Yen CL, Monetti M, Burri BJ, Farese RV, Jr. The triacylglycerol synthesis enzyme DGAT1 also catalyzes the synthesis of diacylglycerols, waxes, and retinyl esters. J Lip Res 2005;46:1502–11.10.1194/jlr.M500036-JLR200Search in Google Scholar PubMed

31. Orland MD, Anwar K, Cromley D, Chu CH, Chen L, Billheimer JT, Hussain MM, Cheng D. Acyl coenzyme a dependent retinol esterification by acyl coenzyme a: diacylglycerol acyltransferase 1. Biochim Biophys Acta 2005;1737:76–82.10.1016/j.bbalip.2005.09.003Search in Google Scholar PubMed

32. Duester G, Mic FA, Molotkov A. Cytosolic retinoid dehydrogenases govern ubiquitous metabolism of retinol to retinaldehyde followed by tissue-specific metabolism to retinoic acid. Chem Biol Interact 2003;143–144:201–10.10.1016/S0009-2797(02)00204-1Search in Google Scholar

33. Ziouzenkova O, Orasanu G, Sharlach M, Akiyama TE, Berger JP, Viereck J, Hamilton JA, Tang G, Dolnikowski GG, Vogel S, Duester G, Plutzky J. Retinaldehyde represses adipogenesis and diet-induced obesity. Nat Med 2007;13:695–702.10.1038/nm1587Search in Google Scholar

34. Zovich DC, Orologa A, Okuno M, Kong LW, Talmage DA, Piantedosi R, Goodman DS, Blaner WS. Differentiation-dependent expression of retinoid-binding proteins in BFC-1 beta adipocytes. J Biol Chem 1992;267:13884–9.10.1016/S0021-9258(19)49651-8Search in Google Scholar

35. Ross AC. Cellular metabolism and activation of retinoids: roles of cellular retinoid-binding proteins. FASEB J 1993;7:317–27.10.1096/fasebj.7.2.8440409Search in Google Scholar PubMed

36. Jamison RS, Newcomer ME, Ong DE. Cellular retinoid-binding proteins: limited proteolysis reveals a conformational change upon ligand binding. Biochemistry 1994;33:2873–9.10.1021/bi00176a017Search in Google Scholar PubMed

37. Napoli JL. A gene knockout corroborates the integral function of cellular retinol-binding protein in retinoid metabolism. Nut Rev 2000;58:230–6.10.1111/j.1753-4887.2000.tb01870.xSearch in Google Scholar PubMed

38. Noy N. Retinoid-binding proteins: mediators of retinoid action. Biochem J 2000;348 Pt 3:481–95.10.1042/bj3480481Search in Google Scholar

39. Storch J, Corsico B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Ann Rev Nut 2008;28:73–95.10.1146/annurev.nutr.27.061406.093710Search in Google Scholar PubMed

40. Odani S, Namba Y, Ishii A, Ono T, Fujii H. Disulfide bonds in rat cutaneous fatty acid-binding protein. J Biochem 2000;128:355–61.10.1093/oxfordjournals.jbchem.a022761Search in Google Scholar PubMed

41. Sima A, Manolescu DC, Bhat P. Retinoids and retinoid-metabolic gene expression in mouse adipose tissues. Biochem Cell Biol 2011;89:578–84.10.1139/o11-062Search in Google Scholar PubMed

42. O’Byrne SM, Wongsiriroj N, Libien J, Vogel S, Goldberg IJ, Baehr W, Palczewski K, Blaner WS. Retinoid absorption and storage is impaired in mice lacking Lecithin:Retinol acyltransferase (LRAT). J Biol Chem 2005;280:35647–57.10.1074/jbc.M507924200Search in Google Scholar PubMed PubMed Central

43. Wei S, Lai K, Patel S, Piantedosi R, Shen H, Colantuoni V, Kraemer FB, Blaner WS. Retinyl ester hydrolysis and retinol efflux from BFC-1beta adipocytes. J Biol Chem 1997;272:14159–65.10.1074/jbc.272.22.14159Search in Google Scholar PubMed

44. Hansson O, Strom K, Guner N, Wierup N, Sundler F, Hoglund P, Holm C. Inflammatory response in white adipose tissue in the non-obese hormone-sensitive lipase null mouse model. J Proteome Res 2006;5:1701–10.10.1021/pr060101hSearch in Google Scholar PubMed

45. Chiefari E, Paonessa F, Iiritano S, Le Pera I, Palmieri D, Brunetti G, Lupo A, Colantuoni V, Foti D, Gulletta E, De Sarro G, Fusco A, Brunetti A. The cAMP-HMGa1-RBP4 system: a novel biochemical pathway for modulating glucose homeostasis. BMC Biology 2009;7:24–37.10.1186/1741-7007-7-24Search in Google Scholar PubMed PubMed Central

46. Kane MA, Folias AE, Napoli JL. HPLC/UV quantitation of retinal, retinol, and retinyl esters in serum and tissues. Anal Biochem 2008;378:71–9.10.1016/j.ab.2008.03.038Search in Google Scholar PubMed PubMed Central

47. Kane MA. Analysis, occurrence, and function of 9-cis-retinoic acid. Biochim Biophys Acta 2012;1821:10–20.10.1016/j.bbalip.2011.09.012Search in Google Scholar PubMed

48. Kurlandsky SB, Gamble MV, Ramakrishnan R, Blaner WS. Plasma delivery of retinoic acid to tissues in the rat. J Biol Chem 1995;270:17850–7.10.1074/jbc.270.30.17850Search in Google Scholar PubMed

49. Sima A, Parisotto M, Mader S, Bhat PV. Kinetic characterization of recombinant mouse retinal dehydrogenase types 3 and 4 for retinal substrates. Biochim Biophysica Acta 2009;1790:1660–4.10.1016/j.bbagen.2009.09.004Search in Google Scholar PubMed

50. Kane MA, Folias AE, Wang C, Napoli JL. Ethanol elevates physiological all-trans-retinoic acid levels in select loci through altering retinoid metabolism in multiple loci: a potential mechanism of ethanol toxicity. FASEB J 2010;24:823–32.10.1096/fj.09-141572Search in Google Scholar PubMed PubMed Central

51. Kiefer FW, Vernochet C, O’Brien P, Spoerl S, Brown JD, Nallamshetty S, Zeyda M, Stulnig TM, Cohen DE, Kahn CR, Plutzky J. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med 2012;18:918–25.10.1038/nm.2757Search in Google Scholar PubMed PubMed Central

52. Leo MA, Kim C, Lieber CS. Increased vitamin A in esophagus and other extrahepatic tissues after chronic ethanol consumption in the rat. Alcohol Clin Exp Res 1986;10:487–92.10.1111/j.1530-0277.1986.tb05128.xSearch in Google Scholar

53. Mobarhan S, Layden TJ, Friedman H, Kunigk A, Donahue P. Depletion of liver and esophageal epithelium vitamin A after chronic moderate ethanol consumption in rats: inverse relation to zinc nutriture. Hepatology 1986;6:615–21.10.1002/hep.1840060411Search in Google Scholar

54. Clugston RD, Blaner WS. The adverse effects of alcohol on vitamin A metabolism. Nutrients 2012;4:356–71.10.3390/nu4050356Search in Google Scholar

55. Ashla AA, Hoshikawa Y, Tsuchiya H, Hashiguchi K, Enjoji M, Nakamuta M, Taketomi A, Maehara Y, Shomori K, Kurimasa A, Hisatome I, Ito H, Shiota G. Genetic analysis of expression profile involved in retinoid metabolism in non-alcoholic fatty liver disease. Hepatol Res 2010;40:594–604.10.1111/j.1872-034X.2010.00646.xSearch in Google Scholar

56. Shaw N, Elholm M, Noy N. Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. J Biol Chem 2003;278:41589–92.10.1074/jbc.C300368200Search in Google Scholar

57. Zhou XE, Suino-Powell KM, Xu Y, Chan CW, Tanabe O, Kruse SW, Reynolds R, Engel JD, Xu HE. The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor. J Biol Chem 2011;286:2877–85.10.1074/jbc.M110.168740Search in Google Scholar

58. Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev 2004;3:950–64.10.1038/nrd1551Search in Google Scholar

59. Leroy P, Nakshatri H, Chambon P. Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element. Proc Natl Acad Sci USA 1991;88:10138–42.10.1073/pnas.88.22.10138Search in Google Scholar

60. Leroy P, Krust A, Zelent A, Mendelsohn C, Garnier JM, Kastner P, Dierich A, Chambon P. Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid. EMBO J 1991;10:59–69.10.1002/j.1460-2075.1991.tb07921.xSearch in Google Scholar

61. Kastner P, Mark M, Chambon P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 1995;83:859–69.10.1016/0092-8674(95)90202-3Search in Google Scholar

62. Haq R, Chytil F. Expression of nuclear retinoic acid receptors in rat adipose tissue. Biochem Biophys Res Commun 1991;176:1539–44.10.1016/0006-291X(91)90462-GSearch in Google Scholar

63. Kamei Y, Kawada T, Kazuki R, Sugimoto E. Retinoic acid receptor gamma 2 gene expression is up-regulated by retinoic acid in 3t3-l1 preadipocytes. Biochem J 1993;293:807–12.10.1042/bj2930807Search in Google Scholar PubMed PubMed Central

64. Villarroya F. Differential effects of retinoic acid on white and brown adipose tissues. An unexpected role for vitamin a derivatives on energy balance. Ann NY Acad Sci 1998;839:190–5.10.1111/j.1749-6632.1998.tb10757.xSearch in Google Scholar PubMed

65. Umesono K, Giguere V, Glass CK, Rosenfeld MG, Evans RM. Retinoic acid and thyroid hormone induce gene expression through a common responsive element. Nature 1988;336: 262–5.10.1038/336262a0Search in Google Scholar PubMed

66. Mahony S, Mazzoni EO, McCuine S, Young RA, Wichterle H, Gifford DK. Ligand-dependent dynamics of retinoic acid receptor binding during early neurogenesis. Genome Biol 2011;12:R2.10.1186/gb-2011-12-1-r2Search in Google Scholar PubMed PubMed Central

67. Moutier E, Ye T, Choukrallah MA, Urban S, Osz J, Chatagnon A, Delacroix L, Langer D, Rochel N, Moras D, Benoit G, Davidson I. Retinoic acid receptors recognize the mouse genome through binding elements with diverse spacing and topology. J Biol Chem 2012;287:26328–41.10.1074/jbc.M112.361790Search in Google Scholar PubMed PubMed Central

68. Vivat-Hannah V, Bourguet W, Gottardis M, Gronemeyer H. Separation of retinoid X receptor homo- and heterodimerization functions. Mol Cell Biol 2003;23:7678–88.10.1128/MCB.23.21.7678-7688.2003Search in Google Scholar PubMed PubMed Central

69. Mukherjee R, Davies PJ, Crombie DL, Bischoff ED, Cesario RM, Jow L, Hamann LG, Boehm MF, Mondon CE, Nadzan AM, Paterniti JR, Jr., Heyman RA. Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists. Nature 1997;386:407–10.10.1038/386407a0Search in Google Scholar PubMed

70. Shulman AI, Mangelsdorf DJ. Retinoid X receptor heterodimers in the metabolic syndrome. N Engl J Med 2005;353:604–15.10.1056/NEJMra043590Search in Google Scholar PubMed

71. Hua S, Kittler R, White KP. Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Cell 2009;137:1259–71.10.1016/j.cell.2009.04.043Search in Google Scholar PubMed PubMed Central

72. Mendoza-Parra MA, Walia M, Sankar M, Gronemeyer H. Dissecting the retinoid-induced differentiation of F9 embryonal stem cells by integrative genomics. Mol Syst Biol 2011;7:538.10.1038/msb.2011.73Search in Google Scholar

73. Ross-Innes CS, Stark R, Holmes KA, Schmidt D, Spyrou C, Russell R, Massie CE, Vowler SL, Eldridge M, Carroll JS. Cooperative interaction between retinoic acid receptor-alpha and estrogen receptor in breast cancer. Genes Dev 2010;24: 171–82.10.1101/gad.552910Search in Google Scholar

74. Pallottini V, Bulzomi P, Galluzzo P, Martini C, Marino M. Estrogen regulation of adipose tissue functions: involvement of estrogen receptor isoforms. Infect Dis Drug Targ 2008;8:52–60.10.2174/187152608784139631Search in Google Scholar

75. Bastien J, Rochette-Egly C. Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene 2004;328:1–16.10.1016/j.gene.2003.12.005Search in Google Scholar

76. Lefebvre P, Benomar Y, Staels B. Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol Metab. 2010;21:676–83.10.1016/j.tem.2010.06.009Search in Google Scholar

77. Lefebvre P, Martin PJ, Flajollet S, Dedieu S, Billaut X, Lefebvre B. Transcriptional activities of retinoic acid receptors. Vitam Horm 2005;70:199–264.10.1016/S0083-6729(05)70007-8Search in Google Scholar

78. Rochette-Egly C. Nuclear receptors: integration of multiple signalling pathways through phosphorylation. Cell Signal 2003;15:355–66.10.1016/S0898-6568(02)00115-8Search in Google Scholar

79. Flajollet S, Rachez C, Ploton M, Schulz C, Gallais R, Metivier R, Pawlak M, Leray A, Issulahi AA, Héliot L, Staels B, Salbert G, Lefebvre P. The elongation complex components BRD4 and MLLT3/AF9 are transcriptional coactivators of nuclear retinoid receptors. PloS One, 2013, in press.10.1371/journal.pone.0064880Search in Google Scholar

80. Bourguet W, Vivat V, Wurtz JM, Chambon P, Gronemeyer H, Moras D. Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. Mol Cell 2000;5:289–98.10.1016/S1097-2765(00)80424-4Search in Google Scholar

81. Heery DM, Kalkhoven E, Hoare S, Parker MG. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 1997;387:733–6.10.1038/42750Search in Google Scholar PubMed

82. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG. The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 1997;387:677–84.10.1038/42652Search in Google Scholar PubMed

83. Blanco JC, Wang IM, Tsai SY, Tsai MJ, O’Malley BW, Jurutka PW, Haussler MR, Ozato K. Transcription factor TFIIb and the vitamin D receptor cooperatively activate ligand-dependent transcription. Proc Natl Acad Sci USA 1995;92:1535–9.10.1073/pnas.92.5.1535Search in Google Scholar PubMed PubMed Central

84. Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 1995;377:454–57.10.1038/377454a0Search in Google Scholar PubMed

85. Rochette-Egly C, Germain P. Dynamic and combinatorial control of gene expression by nuclear retinoic acid receptors (RARS). Nuc Rec Signal 2009;7:e005.10.1621/nrs.07005Search in Google Scholar PubMed PubMed Central

86. Gupta P, Ho PC, Huq MM, Ha SG, Park SW, Khan AA, Tsai NP, Wei LN. Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and sumoylation of nuclear receptor TR2 to suppress OCT4 expression. Proc Natl Acad Sci USA 2008;105:11424–9.10.1073/pnas.0710561105Search in Google Scholar PubMed PubMed Central

87. Alsayed Y, Uddin S, Mahmud N, Lekmine F, Kalvakolanu DV, Minucci S, Bokoch G, Platanias LC. Activation of RAC1 and the p38 mitogen-activated protein kinase pathway in response to all-trans-retinoic acid. J Biol Chem 2001;276: 4012–9.10.1074/jbc.M007431200Search in Google Scholar PubMed

88. Gianni M, Bauer A, Garattini E, Chambon P, Rochette-Egly C. Phosphorylation by p38mapk and recruitment of SUG-1 are required for RA-induced RAR gamma degradation and transactivation. EMBO J 2002;21:3760–9.10.1093/emboj/cdf374Search in Google Scholar PubMed PubMed Central

89. Gaillard E, Bruck N, Brelivet Y, Bour G, Lalevee S, Bauer A, Poch O, Moras D, Rochette-Egly C. Phosphorylation by PKA potentiates retinoic acid receptor alpha activity by means of increasing interaction with and phosphorylation by cyclin h/cdk7. Proc Natl Acad Sci USA 2006;103:9548–53.10.1073/pnas.0509717103Search in Google Scholar PubMed PubMed Central

90. Bruck R, Weiss S, Aeed H, Pines M, Halpern Z, Zvibel I. Additive inhibitory effect of experimentally induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor gamma and retinoic acid receptor. Dig Dis Sci 2009;54:292–9.10.1007/s10620-008-0336-5Search in Google Scholar PubMed

91. Liu Z, Cao W. p38 mitogen-activated protein kinase: a critical node linking insulin resistance and cardiovascular diseases in type 2 diabetes mellitus. Endocr Metab Immune Disord Drug Target 2009;9:38–46.10.2174/187153009787582397Search in Google Scholar PubMed

92. Bastien J, Plassat JL, Payrastre B, Rochette-Egly C. The phosphoinositide 3-kinase/akt pathway is essential for the retinoic acid-induced differentiation of f9 cells. Oncogene 2006;25:2040–7.10.1038/sj.onc.1209241Search in Google Scholar PubMed

93. Alvarez FJ, Murahari S, Couto CG, Rosol TJ, Kulp SK, Chen CS, Kisseberth WC. 3-phosphoinositide-dependent protein kinase-1/akt signalling and inhibition in a canine prostate carcinoma cell line. Vet Comp Oncol 2007;5:47–58.10.1111/j.1476-5829.2006.00117.xSearch in Google Scholar PubMed

94. Monteiro MC, Wdziekonski B, Villageois P, Vernochet C, Iehle C, Billon N, Dani C. Commitment of mouse embryonic stem cells to the adipocyte lineage requires retinoic acid receptor beta and active GSK3. Stem Cells Dev 2009;18:457–63.10.1089/scd.2008.0154Search in Google Scholar PubMed

95. Xue JC, Schwarz EJ, Chawla A, Lazar MA. Distinct stages in adipogenesis revealed by retinoid inhibition of differentiation after induction of PPARgamma. Mol Cell Biol 1996;16: 1567–75.10.1128/MCB.16.4.1567Search in Google Scholar PubMed PubMed Central

96. Schwarz EJ, Reginato MJ, Shao D, Krakow SL, Lazar MA. Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription. Mol Cell Biol 1997;17:1552–61.10.1128/MCB.17.3.1552Search in Google Scholar PubMed PubMed Central

97. Skillington J, Choy L, Derynck R. Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol 2002;159:135–46.10.1083/jcb.200204060Search in Google Scholar PubMed PubMed Central

98. Hisada K, Hata K, Ichida F, Matsubara T, Orimo H, Nakano T, Yatani H, Nishimura R, Yoneda T. Retinoic acid regulates commitment of undifferentiated mesenchymal stem cells into osteoblasts and adipocytes. J Bone Min Metab 2013;31:53–63.10.1007/s00774-012-0385-xSearch in Google Scholar PubMed

99. Dingwall M, Marchildon F, Gunanayagam A, Louis CS, Wiper-Bergeron N. Retinoic acid-induced SMAD3 expression is required for the induction of osteoblastogenesis of mesenchymal stem cells. Differentiation 2011;82:57–65.10.1016/j.diff.2011.05.003Search in Google Scholar PubMed

100. Marchildon F, St-Louis C, Akter R, Roodman V, Wiper-Bergeron NL. Transcription factor SMAD3 is required for the inhibition of adipogenesis by retinoic acid. J Biol Chem 2010;285:13274–84.10.1074/jbc.M109.054536Search in Google Scholar PubMed PubMed Central

101. Sun F, Pan Q, Wang J, Liu S, Li Z, Yu Y. Contrary effects of BMP-2 and ATRA on adipogenesis in mouse mesenchymal fibroblasts. Biochem Genet 2009;47:789–801.10.1007/s10528-009-9277-8Search in Google Scholar PubMed

102. Lee JS, Park JH, Kwon IK, Lim JY. Retinoic acid inhibits BMP4-induced C3H10T1/2 stem cell commitment to adipocyte via downregulating SMAD/p38mapk signaling. Biochem Biophys Res Comm 2011;409:550–5.10.1016/j.bbrc.2011.05.042Search in Google Scholar PubMed

103. Berry DC, DeSantis D, Soltanian H, Croniger CM, Noy N. Retinoic acid upregulates preadipocyte genes to block adipogenesis and suppress diet-induced obesity. Diabetes 2012;61:1112–21.10.2337/db11-1620Search in Google Scholar PubMed PubMed Central

104. Imai T, Jiang M, Chambon P, Metzger D. Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor alpha mediated by a tamoxifen-inducible chimeric CRE recombinase (CRE-ert2) in adipocytes. Proc Natl Acad Sci USA 2001;98:224–8.10.1073/pnas.011528898Search in Google Scholar

105. Canan Koch SS, Dardashti LJ, Cesario RM, Croston GE, Boehm MF, Heyman RA, Nadzan AM. Synthesis of retinoid X receptor-specific ligands that are potent inducers of adipogenesis in 3T3-L1 cells. J Med Chem 1999;42:742–50.10.1021/jm980621rSearch in Google Scholar PubMed

106. Garcia E, Lacasa D, Agli B, Giudicelli Y, Castelli D. Antiadipogenic properties of retinol in primary cultured differentiating human adipocyte precursor cells. Int J Cosmet Sci 2000;22: 95–103.10.1046/j.1467-2494.2000.00018.xSearch in Google Scholar PubMed

107. Ohyama M, Matsuda K, Torii S, Matsui T, Yano H, Kawada T, Ishihara T. The interaction between vitamin a and thiazolidinedione on bovine adipocyte differentiation in primary culture. J Anim Sci 1998;76:61–5.10.2527/1998.76161xSearch in Google Scholar PubMed

108. Berry DC, Noy N. Signaling by vitamin a and retinol-binding protein in regulation of insulin responses and lipid homeostasis. Biochim Biophys Acta 2012;1821:168–76.10.1016/j.bbalip.2011.07.002Search in Google Scholar PubMed PubMed Central

109. Schug TT, Berry DC, Shaw NS, Travis SN, Noy N. Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 2007;129:723–33.10.1016/j.cell.2007.02.050Search in Google Scholar PubMed PubMed Central

110. Schug TT, Berry DC, Toshkov IA, Cheng L, Nikitin AY, Noy N. Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARbeta/delta to RAR. Proc Natl Acad Sci USA 2008;105:7546–51.10.1073/pnas.0709981105Search in Google Scholar PubMed PubMed Central

111. Berry DC, Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol Cell Biol 2009;29:3286–96.10.1128/MCB.01742-08Search in Google Scholar PubMed PubMed Central

112. Berry DC, Soltanian H, Noy N. Repression of cellular retinoic acid-binding protein ii during adipocyte differentiation. J Biol Chem 2010;285:15324–32.10.1074/jbc.M110.110635Search in Google Scholar PubMed PubMed Central

113. Fu M, Sun T, Bookout AL, Downes M, Yu RT, Evans RM, Mangelsdorf DJ. A nuclear receptor atlas: 3t3-l1 adipogenesis. Mol Endo;19:2437–50.10.1210/me.2004-0539Search in Google Scholar PubMed

114. Bairras C, Redonnet A, Dabadie H, Gin H, Atgie C, Pallet V, Higueret P, Noel-Suberville C. RARgamma and TRbeta expressions are decreased in PBMC and sWAT of obese subjects in weight gain. J Physiol Biochem 2010;66:29–37.10.1007/s13105-010-0006-xSearch in Google Scholar PubMed

115. Redonnet A, Bonilla S, Noel-Suberville C, Pallet V, Dabadie H, Gin H, Higueret P. Relationship between peroxisome proliferator-activated receptor gamma and retinoic acid receptor alpha gene expression in obese human adipose tissue. Int J Obes Relat Metab Disord 2002;26:920–7.10.1038/sj.ijo.0802025Search in Google Scholar PubMed

116. Mercader J, Madsen L, Felipe F, Palou A, Kristiansen K, Bonet ML. All-trans retinoic acid increases oxidative metabolism in mature adipocytes. Cell Physiol Biochem 2007;20:1061–72.10.1159/000110717Search in Google Scholar PubMed

117. del Mar Gonzalez-Barroso M, Pecqueur C, Gelly C, Sanchis D, Alves-Guerra MC, Bouillaud F, Ricquier D, Cassard-Doulcier AM. Transcriptional activation of the human ucp1 gene in a rodent cell line. Synergism of retinoids, isoproterenol, and thiazolidinedione is mediated by a multipartite response element. J Biol Chem 2000;275:31722–32.10.1074/jbc.M001678200Search in Google Scholar PubMed

118. Alvarez R, Checa M, Brun S, Vinas O, Mampel T, Iglesias R, Giralt M, Villarroya F. Both retinoic-acid-receptor- and retinoid-X-receptor-dependent signalling pathways mediate the induction of the brown-adipose-tissue-uncoupling-protein-1 gene by retinoids. Biochem J 2000;345 Pt 1:91–7.10.1042/bj3450091Search in Google Scholar

119. Hernandez A, de Mena RM, Martin E, Obregon MJ. Differences in the response of ucp1 mrna to hormonal stimulation between rat and mouse primary cultures of brown adipocytes. Cell Physiol Biochem 2011;28:969–80.10.1159/000335810Search in Google Scholar PubMed

120. Puigserver P, Vazquez F, Bonet ML, Pico C, Palou A. In vitro and in vivo induction of brown adipocyte uncoupling protein (thermogenin) by retinoic acid. Biochem J 1996;317:827–33.10.1042/bj3170827Search in Google Scholar PubMed PubMed Central

121. Rabelo R, Reyes C, Schifman A, Silva JE. A complex retinoic acid response element in the uncoupling protein gene defines a novel role for retinoids in thermogenesis. Endocrinology 1996;137:3488–96.10.1210/endo.137.8.8754778Search in Google Scholar PubMed

122. Rial E, Gonzalez-Barroso M, Fleury C, Iturrizaga S, Sanchis D, Jimenez-Jimenez J, Ricquier D, Goubern M, Bouillaud F. Retinoids activate proton transport by the uncoupling proteins UCP1 and ucp2. The EMBO Journal 1999;18:5827–33.10.1093/emboj/18.21.5827Search in Google Scholar

123. Mercader J, Ribot J, Murano I, Felipe F, Cinti S, Bonet ML, Palou A. Remodeling of white adipose tissue after retinoic acid administration in mice. Endocrinology 2006;147:5325–32.10.1210/en.2006-0760Search in Google Scholar

124. Berry DC, Jin H, Majumdar A, Noy N. Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc Natl Acad Sci U S A 2011;108: 4340–5.10.1073/pnas.1011115108Search in Google Scholar

125. Teruel T, Hernandez R, Benito M, Lorenzo M. Rosiglitazone and retinoic acid induce uncoupling protein-1 (ucp-1) in a p38 mitogen-activated protein kinase-dependent manner in fetal primary brown adipocytes. J Biol Chem 2003;278:263–9.10.1074/jbc.M207200200Search in Google Scholar

126. Carmona MC, Valmaseda A, Iglesias R, Mampel T, Vinas O, Giralt M, Villarroya F. 9-cis retinoic acid induces the expression of the uncoupling protein-2 gene in brown adipocytes. FEBS Lett 1998;441:447–50.10.1016/S0014-5793(98)01598-1Search in Google Scholar

127. Ziouzenkova O, Orasanu G, Sukhova G, Lau E, Berger JP, Tang G, Krinsky NI, Dolnikowski GG, Plutzky J. Asymmetric cleavage of beta-carotene yields a transcriptional repressor of retinoid x receptor and peroxisome proliferator-activated receptor responses. Mol Endo 2007;21:77–88.10.1210/me.2006-0225Search in Google Scholar

128. Reichert B, Yasmeen R, Jeyakumar SM, Yang F, Thomou T, Alder H, Duester G, Maiseyeu A, Mihai G, Harrison EH, Rajagopalan S, Kirkland JL, Ziouzenkova O. Concerted action of aldehyde dehydrogenases influences depot-specific fat formation. Mol Endo 2011;25:799–809.10.1210/me.2010-0465Search in Google Scholar

129. Bray GA, Bellanger T. Epidemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine 2006;29: 109–17.10.1385/ENDO:29:1:109Search in Google Scholar

130. Mensah GA, Mokdad AH, Ford E, Narayan KM, Giles WH, Vinicor F, Deedwania PC. Obesity, metabolic syndrome, and type 2 diabetes: emerging epidemics and their cardiovascular implications. Cardiol Clin 2004;22:485–504.10.1016/j.ccl.2004.06.005Search in Google Scholar PubMed

131. Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005;436:356–62.10.1038/nature03711Search in Google Scholar PubMed

132. Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Eng J Med 2006;354:2552–63.10.1056/NEJMoa054862Search in Google Scholar PubMed

133. Kloting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, Fasshauer M, Schon MR, Stumvoll M, Bluher M, Kahn BB. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab 2007;6:79–87.10.1016/j.cmet.2007.06.002Search in Google Scholar PubMed

134. Erikstrup C, Mortensen OH, Nielsen AR, Fischer CP, Plomgaard P, Petersen AM, Krogh-Madsen R, Lindegaard B, Erhardt JG, Ullum H, Benn CS, Pedersen BK. RBP-to-retinol ratio, but not total RBP, is elevated in patients with type 2 diabetes. Diabetes Obes Metab 2009;11:204–212.10.1111/j.1463-1326.2008.00901.xSearch in Google Scholar PubMed

135. Villarroya F, Iglesias R, Giralt M. Retinoids and retinoid receptors in the control of energy balance: novel pharmacological strategies in obesity and diabetes. Curr Med Chem 2004;11:795–805.10.2174/0929867043455747Search in Google Scholar PubMed

136. Chu EW, Malmgren RA. An inhibitory effect of vitamin A on the induction of tumors of forestomach and cervix in the Syrian hamster by carcinogenic polycyclic hydrocarbons. Cancer Res 1965;25:884–95.Search in Google Scholar

137. Rowe NH, Gorlin RJ. The effect of vitamin A deficiency upon experimental oral carcinogenesis. J Dent Res 1959;38:72–83.10.1177/00220345590380012601Search in Google Scholar PubMed

138. Lippman SM, Kessler JF, Meyskens FL, Jr. Retinoids as preventive and therapeutic anticancer agents. Cancer Treat Rep 1987;71:493–515.Search in Google Scholar

139. Lippman SM, Kessler JF, Meyskens FL, Jr. Retinoids as preventive and therapeutic anticancer agents. Cancer Treat Rep 1987;71:391–405.Search in Google Scholar

140. Benbrook D, Lernhardt E, Pfahl M. A new retinoic acid receptor identified from a hepatocellular carcinoma. Nature 1988;333:669–672.10.1038/333669a0Search in Google Scholar PubMed

141. Hong WK, Benner SE, Lippman SM. Evolution of aerodigestive tract 13-cis-retinoid acid chemoprevention: the M.D. Anderson experience. Leukemia 1994;8 Suppl 3:S33–7.Search in Google Scholar

142. Patatanian E, Thompson DF. Retinoic acid syndrome: a review. J Clin Pharm Ther 2008;33:331–8.10.1111/j.1365-2710.2008.00935.xSearch in Google Scholar PubMed

143. Holmes D, Vishnu P, Dorer RK, Aboulafia DM. All-trans retinoic acid-induced pseudotumor cerebri during induction therapy for acute promyelocytic leukemia: a case report and literature review. Case Rep Oncol Med 2012;2012:313057.10.1155/2012/313057Search in Google Scholar PubMed PubMed Central

144. Fukasawa H, Nakagomi M, Yamagata N, Katsuki H, Kawahara K, Kitaoka K, Miki T, Shudo K. Tamibarotene: a candidate retinoid drug for Alzheimer’s disease. Biol Pharm Bull 2012;35: 1206–12.10.1248/bpb.b12-00314Search in Google Scholar PubMed

145. Guleria RS, Singh AB, Nizamutdinova IT, Souslova T, Mohammad AA, Kendall JA, Jr., Baker KM, Pan J. Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats. J Mol Cell Cardiol 2013;57:106–18.10.1016/j.yjmcc.2013.01.017Search in Google Scholar PubMed PubMed Central

146. Corbetta S, Angioni R, Cattaneo A, Beck-Peccoz P, Spada A. Effects of retinoid therapy on insulin sensitivity, lipid profile and circulating adipocytokines. Eur J Endocr 2006;154: 83–6.10.1530/eje.1.02057Search in Google Scholar PubMed

147. Jones PH, Burnett RD, Fainaru I, Nadolny P, Walker P, Yu Z, Tang-Liu D, Ganesan TS, Talbot DC, Harris AL, Rustin GJ. A phase 1 study of tazarotene in adults with advanced cancer. B J Can 2003;89:808–15.10.1038/sj.bjc.6601169Search in Google Scholar PubMed PubMed Central

148. Klor HU, Weizel A, Augustin M, Diepgen TL, Elsner P, Homey B, Kapp A, Ruzicka T, Luger T. The impact of oral vitamin a derivatives on lipid metabolism – what recommendations can be derived for dealing with this issue in the daily dermatological practice? J Dtsch Dermatol Ges 2011;9:600–6.10.1111/j.1610-0387.2011.07637.xSearch in Google Scholar PubMed

149. Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degos L. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 1990;76:1704–9.10.1182/blood.V76.9.1704.1704Search in Google Scholar

150. Conley BA, Egorin MJ, Sridhara R, Finley R, Hemady R, Wu S, Tait NS, Van Echo DA. Phase i clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics. Can Chemother Pharm 1997;39:291–9.10.1007/s002800050575Search in Google Scholar PubMed

151. Rizvi NA, Marshall JL, Ness E, Hawkins MJ, Kessler C, Jacobs H, Brenckman WD, Jr., Lee JS, Petros W, Hong WK, Kurie JM. Initial clinical trial of oral TAC-101, a novel retinoic acid receptor-alpha selective retinoid, in patients with advanced cancer. J Clin Oncol 2002;20:3522–32.10.1200/JCO.2002.02.090Search in Google Scholar PubMed

152. Langin D. Recruitment of brown fat and conversion of white into brown adipocytes: strategies to fight the metabolic complications of obesity? Biochimica Biophysica Acta 2010;1801:372–6.10.1016/j.bbalip.2009.09.008Search in Google Scholar PubMed

153. Schulz TJ, Huang TL, Tran TT, Zhang H, Townsend KL, Shadrach JL, Cerletti M, McDougall LE, Giorgadze N, Tchkonia T, Schrier D, Falb D, Kirkland JL, Wagers AJ, Tseng YH. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc Natl Acad Sci USA 2011;108:143–8.10.1073/pnas.1010929108Search in Google Scholar PubMed PubMed Central

154. Vegiopoulos A, Muller-Decker K, Strzoda D, Schmitt I, Chichelnitskiy E, Ostertag A, Berriel Diaz M, Rozman J, Hrabe de Angelis M, Nusing RM, Meyer CW, Wahli W, Klingenspor M, Herzig S. Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes. Science 2010;328:1158–61.10.1126/science.1186034Search in Google Scholar PubMed

155. Altucci L, Leibowitz MD, Ogilvie KM, de Lera AR, Gronemeyer H. RAR and RXR modulation in cancer and metabolic disease. Nature Rev 2007;6:793–810.10.1038/nrd2397Search in Google Scholar PubMed

156. Curley RW, Jr. Retinoid chemistry: synthesis and application for metabolic disease. Biochim Biophys Acta 2012;1821:3–9.10.1016/j.bbalip.2011.04.007Search in Google Scholar

157. Lalloyer F, Pedersen TA, Gross B, Lestavel S, Yous S, Vallez E, Gustafsson JA, Mandrup S, Fievet C, Staels B, Tailleux A. Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver. Arterioscler Thromb Vasc Biol 2009;29:1488–95.10.1161/ATVBAHA.109.189506Search in Google Scholar

158. Leibowitz MD, Ardecky RJ, Boehm MF, Broderick CL, Carfagna MA, Crombie DL, D’Arrigo J, Etgen GJ, Faul MM, Grese TA, Havel H, Hein NI, Heyman RA, Jolley D, Klausing K, Liu S, Mais DE, Mapes CM, Marschke KB, Michellys PY, Montrose-Rafizadeh C, Ogilvie KM, Pascual B, Rungta D, Tyhonas JS, Urcan MS, Wardlow M, Yumibe N, Reifel-Miller A. Biological characterization of a heterodimer-selective retinoid X receptor modulator: potential benefits for the treatment of type 2 diabetes. Endocrinology 2006;147:1044–53.10.1210/en.2005-0690Search in Google Scholar

159. Forman BM. The antidiabetic agent LG100754 sensitizes cells to low concentrations of peroxisome proliferator-activated receptor gamma ligands. J Biol Chem 2002;277:12503–6.10.1074/jbc.C200004200Search in Google Scholar

160. Mavligit GM, Zukiwski AA, Charnsangavej C, Carrasco CH, Wallace S, Gutterman JU. Regional biologic therapy. Hepatic arterial infusion of recombinant human tumor necrosis factor in patients with liver metastases. Cancer 1992;69: 557–61.10.1002/1097-0142(19920115)69:2<557::AID-CNCR2820690246>3.0.CO;2-QSearch in Google Scholar

161. Perez E, Bourguet W, Gronemeyer H, de Lera AR. Modulation of RXR function through ligand design. Biochim Biophys Acta 2012;1821:57–69.10.1016/j.bbalip.2011.04.003Search in Google Scholar