The mitochondrial uncoupling protein (UCP) is responsible for the thermogenic function of brown fat, and it is a molecular marker of the brown adipocyte cell type. Retinoic acid (RA) increased UCP mRNA levels severalfold in brown adipocytes differentiated in culture. This induction was independent of adrenergic pathways or protein synthesis. RA stimulated ucp gene expression regardless of the stage of brown adipocyte differentiation. In transient transfection experiments RA induced the expression of chloramphenicol acetyltransferase vectors driven by 4.5 kilobases of the 5`-noncoding region of the rat ucp gene, and co-transfection of expression vectors for RA receptors enhanced the action of RA. Retinoic acid receptor was more effective than retinoid X receptor in promoting RA action, whereas a mixture of the two was the most effective. The RA-responsive region in the ucp gene was located at -2469/-2318 and contains three motifs (between -2357 and -2330) of the consensus half-sites characteristic of retinoic acid response elements. This 27-base pair sequence specifically binds purified retinoic acid receptor as well as related proteins from brown fat nuclei. In conclusion, a novel potential regulatory pathway of brown fat development and thermogenic function has been recognized by identifying RA as a transcriptional activator of the ucp gene.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				D. Debevec, M. Christian, D. Morganstein, A. Seth, B. Herzog, M. Parker, and R. White Receptor Interacting Protein 140 Regulates Expression of Uncoupling Protein 1 in Adipocytes through Specific Peroxisome Proliferator Activated Receptor Isoforms and Estrogen-Related Receptor {alpha} Mol. Endocrinol., July 1, 2007; 21(7): 1581 - 1592. [Abstract] [Full Text] [PDF]

				J. Mercader, J. Ribot, I. Murano, F. Felipe, S. Cinti, M. L. Bonet, and A. Palou Remodeling of White Adipose Tissue after Retinoic Acid Administration in Mice Endocrinology, November 1, 2006; 147(11): 5325 - 5332. [Abstract] [Full Text] [PDF]

				E. Hondares, O. Mora, P. Yubero, M. R. de la Concepcion, R. Iglesias, M. Giralt, and F. Villarroya Thiazolidinediones and Rexinoids Induce Peroxisome Proliferator-Activated Receptor-Coactivator (PGC)-1{alpha} Gene Transcription: An Autoregulatory Loop Controls PGC-1{alpha} Expression in Adipocytes via Peroxisome Proliferator-Activated Receptor-{gamma} Coactivation Endocrinology, June 1, 2006; 147(6): 2829 - 2838. [Abstract] [Full Text] [PDF]

				S M Jeyakumar, A Vajreswari, B Sesikeran, and N V Giridharan Vitamin A supplementation induces adipose tissue loss through apoptosis in lean but not in obese rats of the WNIN/Ob strain J. Mol. Endocrinol., October 1, 2005; 35(2): 391 - 398. [Abstract] [Full Text] [PDF]

				G. Leonardsson, J. H. Steel, M. Christian, V. Pocock, S. Milligan, J. Bell, P.-W. So, G. Medina-Gomez, A. Vidal-Puig, R. White, et al. Nuclear receptor corepressor RIP140 regulates fat accumulation PNAS, June 1, 2004; 101(22): 8437 - 8442. [Abstract] [Full Text] [PDF]

				F. Felipe, M. L. Bonet, J. Ribot, and A. Palou Modulation of Resistin Expression by Retinoic Acid and Vitamin A Status Diabetes, April 1, 2004; 53(4): 882 - 889. [Abstract] [Full Text] [PDF]

				B. CANNON and J. NEDERGAARD Brown Adipose Tissue: Function and Physiological Significance Physiol Rev, January 1, 2004; 84(1): 277 - 359. [Abstract] [Full Text] [PDF]

				M. Arribas, A. M. Valverde, and M. Benito Role of IRS-3 in the Insulin Signaling of IRS-1-deficient Brown Adipocytes J. Biol. Chem., November 14, 2003; 278(46): 45189 - 45199. [Abstract] [Full Text] [PDF]

				A. M. Valverde, M. Arribas, C. Mur, P. Navarro, S. Pons, A.-M. Cassard-Doulcier, C. R. Kahn, and M. Benito Insulin-induced Up-regulated Uncoupling Protein-1 Expression Is Mediated by Insulin Receptor Substrate 1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Fetal Brown Adipocytes J. Biol. Chem., March 14, 2003; 278(12): 10221 - 10231. [Abstract] [Full Text] [PDF]

				J. S. Rim and L. P. Kozak Regulatory Motifs for CREB-binding Protein and Nfe2l2 Transcription Factors in the Upstream Enhancer of the Mitochondrial Uncoupling Protein 1 Gene J. Biol. Chem., September 6, 2002; 277(37): 34589 - 34600. [Abstract] [Full Text] [PDF]

				M. C. Carmona, R. Iglesias, M.-J. Obregon, G. J. Darlington, F. Villarroya, and M. Giralt Mitochondrial Biogenesis and Thyroid Status Maturation in Brown Fat Require CCAAT/Enhancer-binding Protein alpha J. Biol. Chem., June 7, 2002; 277(24): 21489 - 21498. [Abstract] [Full Text] [PDF]

				H. Oberkofler, H. Esterbauer, V. Linnemayr, A. D. Strosberg, F. Krempler, and W. Patsch Peroxisome Proliferator-activated Receptor (PPAR) gamma Coactivator-1 Recruitment Regulates PPAR Subtype Specificity J. Biol. Chem., May 3, 2002; 277(19): 16750 - 16757. [Abstract] [Full Text] [PDF]

				S. Viengchareun, P. Penfornis, M.-C. Zennaro, and M. Lombes Mineralocorticoid and glucocorticoid receptors inhibit UCP expression and function in brown adipocytes Am J Physiol Endocrinol Metab, April 1, 2001; 280(4): E640 - E649. [Abstract] [Full Text] [PDF]

				A. Hernandez and M. J. Obregon Triiodothyronine amplifies the adrenergic stimulation of uncoupling protein expression in rat brown adipocytes Am J Physiol Endocrinol Metab, May 1, 2000; 278(5): E769 - E777. [Abstract] [Full Text] [PDF]

				M. V. Kumar, G. D. Sunvold, and P. J. Scarpace Dietary vitamin A supplementation in rats: suppression of leptin and induction of UCP1 mRNA J. Lipid Res., May 1, 1999; 40(5): 824 - 829. [Abstract] [Full Text]

				P. Yubero, M. Barberá, R. Alvarez, O. Viñas, T. Mampel, R. Iglesias, F. Villarroya, and M. Giralt Dominant Negative Regulation by c-Jun of Transcription of the Uncoupling Protein-1 Gene through a Proximal cAMP-Regulatory Element: A Mechanism for Repressing Basal and Norepinephrine-Induced Expression of the Gene before Brown Adipocyte Differentiation Mol. Endocrinol., July 1, 1998; 12(7): 1023 - 1037. [Abstract] [Full Text]

				F. VILLARROYA Differential Effects of Retinoic Acid on White and Brown Adipose Tissues: An Unexpected Role for Vitamin A Derivatives on Energy Balance Ann. N.Y. Acad. Sci., May 15, 1998; 839(1): 190 - 195. [Full Text] [PDF]

				M. Larose, A.-M. Cassard-Doulcier, C. Fleury, F. Serra, O. Champigny, F. Bouillaud, and D. Ricquier Essential cis-Acting Elements in Rat Uncoupling Protein Gene Are in an Enhancer Containing a Complex Retinoic Acid Response Domain J. Biol. Chem., December 6, 1996; 271(49): 31533 - 31542. [Abstract] [Full Text] [PDF]

				T.-A. C. Tai, C. Jennermann, K. K. Brown, B. B. Oliver, M. A. MacGinnitie, W. O. Wilkison, H. R. Brown, J. M. Lehmann, S. A. Kliewer, D. C. Morris, et al. Activation of the Nuclear Receptor Peroxisome Proliferator-activated Receptor gamma Promotes Brown Adipocyte Differentiation J. Biol. Chem., November 22, 1996; 271(47): 29909 - 29914. [Abstract] [Full Text] [PDF]

				M. del Mar Gonzalez-Barroso, C. Pecqueur, C. Gelly, D. Sanchis, M.-C. Alves-Guerra, F. Bouillaud, D. Ricquier, and A.-M. Cassard-Doulcier 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., October 6, 2000; 275(41): 31722 - 31732. [Abstract] [Full Text] [PDF]

				M. J. Barbera, A. Schluter, N. Pedraza, R. Iglesias, F. Villarroya, and M. Giralt Peroxisome Proliferator-activated Receptor alpha Activates Transcription of the Brown Fat Uncoupling Protein-1 Gene. A LINK BETWEEN REGULATION OF THE THERMOGENIC AND LIPID OXIDATION PATHWAYS IN THE BROWN FAT CELL J. Biol. Chem., January 5, 2001; 276(2): 1486 - 1493. [Abstract] [Full Text] [PDF]