Regulation of the uncoupling protein gene expression

Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada.

Uncoupling protein (UCP) is essential to the thermogenic function of brown adipose tissue (BAT). The thermogenic role of this protein is due to its capacity to uncouple oxidative phosphorylation in a regulated manner. The thermogenic potential of BAT is determined by its content of UCP. The gene encoding this protein is under complex regulation. Catecholamines, via cAMP, thyroid hormone and retinoic acid, directly stimulate the gene acting upon an upstream (-2.28/-2.49 kb) enhancer sequence, but cAMP may act upon other sequences of the gene as well. CCAAT enhancer binding proteins and peroxisome proliferation activator receptor (PPAR) gamma 2 have also been implicated in the regulation of the gene acting on discrete sequences. While the thyroid hormone response and retinoic acid response elements (TRE and RARE) have been well defined, the cAMP response elements (CRE) remain elusive. The two TREs are 27 bp apart between -2.33 kb and -2.39 kb. The synergism between cAMP and thyroid hormone seems to reside in a 39 bp sequence downstream (-2.28/-2.32 kb). The most important CRE, the RARE, a cell-specific enhancer and a putative PPAR element are all concentrated in a 90 bp regulatory element of great complexity (-2.40/-2.49 kb). Other hormones, such as insulin and glucocorticoids, and IGF-I also modulate the expression of the gene but their effects seem to be largely indirect. Understanding the regulation of the UCP gene expression may facilitate the development of interventions in obesity and related disorders.

This article has been cited by other articles:

				G. Medina-Gomez, R. M. Calvo, and M.-J. Obregon Thermogenic effect of triiodothyroacetic acid at low doses in rat adipose tissue without adverse side effects in the thyroid axis Am J Physiol Endocrinol Metab, April 1, 2008; 294(4): E688 - E697. [Abstract] [Full Text] [PDF]

				M. Jastroch, K. W. Withers, S. Taudien, P. B. Frappell, M. Helwig, T. Fromme, V. Hirschberg, G. Heldmaier, B. M. McAllan, B. T. Firth, et al. Marsupial uncoupling protein 1 sheds light on the evolution of mammalian nonshivering thermogenesis Physiol Genomics, January 17, 2008; 32(2): 161 - 169. [Abstract] [Full Text] [PDF]

				A. Voss-Andreae, J. G. Murphy, K. L. J. Ellacott, R. C. Stuart, E. A. Nillni, R. D. Cone, and W. Fan Role of the Central Melanocortin Circuitry in Adaptive Thermogenesis of Brown Adipose Tissue Endocrinology, April 1, 2007; 148(4): 1550 - 1560. [Abstract] [Full Text] [PDF]

				Y.-Y. Liu, R. S. Heymann, F. Moatamed, J. J. Schultz, D. Sobel, and G. A. Brent A Mutant Thyroid Hormone Receptor {alpha} Antagonizes Peroxisome Proliferator-Activated Receptor {alpha} Signaling in Vivo and Impairs Fatty Acid Oxidation Endocrinology, March 1, 2007; 148(3): 1206 - 1217. [Abstract] [Full Text] [PDF]

				J. E. Silva Thermogenic Mechanisms and Their Hormonal Regulation Physiol Rev, April 1, 2006; 86(2): 435 - 464. [Abstract] [Full Text] [PDF]

				J C Sousa, G M. de Escobar, P Oliveira, M J Saraiva, and J A Palha Transthyretin is not necessary for thyroid hormone metabolism in conditions of increased hormone demand J. Endocrinol., November 1, 2005; 187(2): 257 - 266. [Abstract] [Full Text] [PDF]

				H. Marrif, A. Schifman, Z. Stepanyan, M.-A. Gillis, A. Calderone, R. E. Weiss, J. Samarut, and J. E. Silva Temperature Homeostasis in Transgenic Mice Lacking Thyroid Hormone Receptor-{alpha} Gene Products Endocrinology, July 1, 2005; 146(7): 2872 - 2884. [Abstract] [Full Text] [PDF]

				W. Cao, K. W. Daniel, J. Robidoux, P. Puigserver, A. V. Medvedev, X. Bai, L. M. Floering, B. M. Spiegelman, and S. Collins p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene Mol. Cell. Biol., April 1, 2004; 24(7): 3057 - 3067. [Abstract] [Full Text] [PDF]

				V. Golozoubova, H. Gullberg, A. Matthias, B. Cannon, B. Vennstrom, and J. Nedergaard Depressed Thermogenesis but Competent Brown Adipose Tissue Recruitment in Mice Devoid of All Hormone-Binding Thyroid Hormone Receptors Mol. Endocrinol., February 1, 2004; 18(2): 384 - 401. [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]

				J. E. Silva The Thermogenic Effect of Thyroid Hormone and Its Clinical Implications Ann Intern Med, August 5, 2003; 139(3): 205 - 213. [Full Text] [PDF]

				R. P. Peeters, H. van Toor, W. Klootwijk, Y. B. de Rijke, G. G. J. M. Kuiper, A. G. Uitterlinden, and T. J. Visser Polymorphisms in Thyroid Hormone Pathway Genes Are Associated with Plasma TSH and Iodothyronine Levels in Healthy Subjects J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2880 - 2888. [Abstract] [Full Text] [PDF]

				T. Teruel, R. Hernandez, M. Benito, and M. Lorenzo 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., January 3, 2003; 278(1): 263 - 269. [Abstract] [Full Text] [PDF]

				C. Fekete, S. Sarkar, W. M. Rand, J. W. Harney, C. H. Emerson, A. C. Bianco, and R. M. Lechan Agouti-Related Protein (AGRP) Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid (HPT) Axis; Comparisons between the Effect of AGRP and Neuropeptide Y on Energy Homeostasis and the HPT Axis Endocrinology, October 1, 2002; 143(10): 3846 - 3853. [Abstract] [Full Text] [PDF]

				A. C. Bianco, D. Salvatore, B. Gereben, M. J. Berry, and P. R. Larsen Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases Endocr. Rev., February 1, 2002; 23(1): 38 - 89. [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]

				M. Murakami, Y. Kamiya, T. Morimura, O. Araki, M. Imamura, T. Ogiwara, H. Mizuma, and M. Mori Thyrotropin Receptors in Brown Adipose Tissue: Thyrotropin Stimulates Type II Iodothyronine Deiodinase and Uncoupling Protein-1 in Brown Adipocytes Endocrinology, March 1, 2001; 142(3): 1195 - 1201. [Abstract] [Full Text] [PDF]

				H. Mizuma, M. Murakami, and M. Mori Thyroid Hormone Activation in Human Vascular Smooth Muscle Cells : Expression of Type II Iodothyronine Deiodinase Circ. Res., February 16, 2001; 88(3): 313 - 318. [Abstract] [Full Text] [PDF]

				L. D. Klaman, O. Boss, O. D. Peroni, J. K. Kim, J. L. Martino, J. M. Zabolotny, N. Moghal, M. Lubkin, Y.-B. Kim, A. H. Sharpe, et al. Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice Mol. Cell. Biol., August 1, 2000; 20(15): 5479 - 5489. [Abstract] [Full Text]

				J. Klein, M. Fasshauer, M. Benito, and C. R. Kahn Insulin and the {beta}3-Adrenoceptor Differentially Regulate Uncoupling Protein-1 Expression Mol. Endocrinol., June 1, 2000; 14(6): 764 - 773. [Abstract] [Full Text]

				G. A. Bray and F. L. Greenway Current and Potential Drugs for Treatment of Obesity Endocr. Rev., December 1, 1999; 20(6): 805 - 875. [Abstract] [Full Text]

				S. P. Commins, D. J. Marsh, S. A. Thomas, P. M. Watson, M. A. Padgett, R. Palmiter, and T. W. Gettys Norepinephrine Is Required for Leptin Effects on Gene Expression in Brown and White Adipose Tissue Endocrinology, October 1, 1999; 140(10): 4772 - 4778. [Abstract] [Full Text]

				L. Poretsky, N. A. Cataldo, Z. Rosenwaks, and L. C. Giudice The Insulin-Related Ovarian Regulatory System in Health and Disease Endocr. Rev., August 1, 1999; 20(4): 535 - 582. [Abstract] [Full Text] [PDF]

				S. P. Commins, P. M. Watson, M. A. Padgett, A. Dudley, G. Argyropoulos, and T. W. Gettys Induction of Uncoupling Protein Expression in Brown and White Adipose Tissue by Leptin Endocrinology, January 1, 1999; 140(1): 292 - 300. [Abstract] [Full Text]

				M. Branco, M. Ribeiro, N. Negrao, and A. C. Bianco 3,5,3'-Triiodothyronine actively stimulates UCP in brown fat under minimal sympathetic activity Am J Physiol Endocrinol Metab, January 1, 1999; 276(1): E179 - E187. [Abstract] [Full Text] [PDF]

				L. J. Kelly, P. P. Vicario, G. M. Thompson, M. R. Candelore, T. W. Doebber, J. Ventre, M. S. Wu, R. Meurer, M. J. Forrest, M. W. Conner, et al. Peroxisome Proliferator-Activated Receptors {gamma} and {alpha} Mediate in Vivo Regulation of Uncoupling Protein (UCP-1, UCP-2, UCP-3) Gene Expression Endocrinology, December 1, 1998; 139(12): 4920 - 4927. [Abstract] [Full Text] [PDF]

				D. Salvatore, T. Bartha, and P. R. Larsen The Guanosine Monophosphate Reductase Gene Is Conserved in Rats and Its Expression Increases Rapidly in Brown Adipose Tissue during Cold Exposure J. Biol. Chem., November 20, 1998; 273(47): 31092 - 31096. [Abstract] [Full Text] [PDF]

				R. Rabelo, A. Camirand, and J. E. Silva 3',5'-Cyclic Adenosine Monophosphate-Response Sequences of the Uncoupling Protein Gene Are Sequentially Recruited During Darglitazone-Induced Brown Adipocyte Differentiation Endocrinology, December 1, 1997; 138(12): 5325 - 5332. [Abstract] [Full Text] [PDF]

				D.-W. Gong, Y. He, M. Karas, and M. Reitman Uncoupling Protein-3 Is a Mediator of Thermogenesis Regulated by Thyroid Hormone, beta 3-Adrenergic Agonists, and Leptin J. Biol. Chem., September 26, 1997; 272(39): 24129 - 24132. [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]

				W. Cao, A. V. Medvedev, K. W. Daniel, and S. Collins beta -Adrenergic Activation of p38 MAP Kinase in Adipocytes. cAMP INDUCTION OF THE UNCOUPLING PROTEIN 1 (UCP1) GENE REQUIRES p38 MAP KINASE J. Biol. Chem., July 13, 2001; 276(29): 27077 - 27082. [Abstract] [Full Text] [PDF]

				A. J. Vidal-Puig, D. Grujic, C.-Y. Zhang, T. Hagen, O. Boss, Y. Ido, A. Szczepanik, J. Wade, V. Mootha, R. Cortright, et al. Energy Metabolism in Uncoupling Protein 3 Gene Knockout Mice J. Biol. Chem., May 19, 2000; 275(21): 16258 - 16266. [Abstract] [Full Text] [PDF]