Hostname: page-component-cd9895bd7-7cvxr Total loading time: 0 Render date: 2024-12-28T19:53:59.446Z Has data issue: false hasContentIssue false
  • English
  • Français

Uncoupling proteins: their roles in adaptive thermogenesis and substrate metabolism reconsidered

Published online by Cambridge University Press:  09 March 2007

Abdul G. Dulloo  and
Sonia Samec
Abdul G. Dulloo*
Affiliation:
Institute of Physiology, Department of Medicine, University of Fribourg, Rue du Musee, Switzerland
Sonia Samec
Affiliation:
Institute of Physiology, Department of Medicine, University of Fribourg, Rue du Musee, Switzerland
*
*Corresponding author: Dr Abdul G. Dulloo, fax +41 26 300 97 34, email abdul.dulloo@unifr.ch
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

During the past few years, there have been two major developments, if not revolutions, in the field of energy balance and weight regulation. The first at the molecular level, which was catalysed by developments in DNA screening technology together with the mapping of the human genome, has been the tremendous advances made in the identification of molecules that play a role in the control of food intake and metabolic rate. The second, at the systemic level, which centered upon the use of modern technologies or more robust analytical techniques for assessing human energy expenditure in response to starvation and overfeeding, has been the publication of several papers providing strong evidence that adaptive thermogenesis plays a much more important role in the regulation of body weight and body composition than previously thought. Within these same few years, several new members of the mitochondrial carrier protein family have been identified in a variety of tissues and organs. All apparently possess uncoupling properties in genetically-modified systems, with two of them (uncoupling protein (UCP) 2 and UCP3) being expressed in adipose tissues and skeletal muscles, which are generally recognised as important sites for variations in thermogenesis and/or in substrate oxidation. Considered as breakthrough discoveries, the cloning of these genes has generated considerable optimism for rapid advances in our molecular understanding of adaptive thermogenesis, and for the identification of new targets for pharmacological management of obesity and cachexia. The present paper traces first, from a historical perspective, the landmark events in the field of thermogenesis that led to the identification of these genes encoding candidate UCP, and then addresses the controversies and on-going debate about their physiological importance in adaptive thermogenesis, in lipid oxidation or in oxidative stress. The general conclusion is that UCP2 and UCP3 may have distinct primary functions, with UCP3 implicated in regulating the flux of lipid substrates across the mitochondria and UCP2 in the control of mitochondrial generation of reactive oxygen species. The distinct functions of these two UCP1 homologues have been incorporated in a conceptual model to illustrate how UCP2 and UCP3 may act in concert in the overall regulation of lipid oxidation concomitant to the prevention of lipid-induced oxidative damage.

Keywords

PDO cheesesMilk traitsMilk compositionChangeable factors in milk
Type
Review article
Information
British Journal of Nutrition , Volume 86 , Issue 2 , August 2001 , pp. 123 - 139
Copyright
Copyright © The Nutrition Society 2001

References

Acheson, KJ, Jéquier, E & Wahren, J (1983) Influence of β-adrenergic blockade on glucose-induced thermogenesis in man. Journal of Clinical Investigation 72, 981–986.CrossRefGoogle ScholarPubMed
Arch, JRS, Ainsworth, AT, Cawthorne, MA, Piercy, V, Sennit, MV, Thody, VE, Wilson, C & Wilson, S (1984) Atypical β-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature 309, 163–165.CrossRefGoogle ScholarPubMed
Ardawi, MS, Majzoub, MF, Masoud, IM & Newsholme, EA (1989) Enzymatic and metabolic adaptations in the gastrocnemius, plantaris and soleus muscles of hypocaloric rats. Biochemical Journal 264, 219–225.Google Scholar
Argyropoulos, G, Brown, AM, Willi, SM, Zhu, J, He, Y, Reitman, M, Spruill, SM & Garvey, WT (1998) Effects of mutations in the human uncoupling protein 3 gene on the respiratory quotient and fat oxidation in severe obesity and type 2 diabetes. Journal of Clinical Investigation 102, 1345–1351.CrossRefGoogle ScholarPubMed
Arsenijevic, D, Onuma, H, Pecqueur, C, Raimbault, S, Manning, BS, Miroux, B, Couplan, E, Alves-Guerra, MC, Goubern, M, Surwit, R, Bouillaud, F, Richard, D, Collins, S & Ricquier, D et al. (2000) Disruption of the uncoupling-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature and Genetics 26, 435–439.CrossRefGoogle Scholar
Astrup, A, MacDonald, IA, (1998) Sympathoadrenal system and metabolism. In Handbook of Obesity, pp. 491–511.[Bray, GA, Bouchard, C and James, WPT, editors]. New York, NY: Marcel Dekker Inc.Google Scholar
Astrup, A, Toubro, S, Dalgaard, LT, Urhammer, SA, Sorensen, TIA & Pedersen, O (1999) Impact of the v/v 55 polymorphism of the uncoupling protein 2 gene on 24-h energy expenditure and substrate oxidation. International Journal of Obesity 23, 1030–1034.CrossRefGoogle Scholar
Berry, MN, Clark, DG, Grivell, AR & Wallace, PG (1985) The contribution of hepatic metabolism to diet-induced thermogenesis. Metabolism 34, 141–147.Google Scholar
Berson, A, De Beco, V, Letteron, P, Robin, MA, Moreau, C, El Kahwaji, J, Verthier, N, Feldmann, G, Fromenty, B & Pessayre, D (1998) Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology 114, 764–774.Google Scholar
Boss, O, Samec, S, Paoloni-Giacobino, A, Rossier, C, Dulloo, AG, Seydoux, J, Muzzin, P & Giacobino, JP (1997) Uncoupling protein-3: A new member of the mitochondrial carrier family with tissue-specific expression. FEBS Letters 408, 39–42.CrossRefGoogle ScholarPubMed
Boss, O, Hagen, T & Lowell, BB (2000) Uncoupling proteins 2 and 3: potential regulators of mitochondrial energy metabolism. Diabetes 49, 143–156.CrossRefGoogle ScholarPubMed
Brand, M, Brindle, KM, Buckingham, JA, Harper, JA, Rolfe, DFS & Stuart, JA (1999) The significance and mechanism of mitochondrial proton conductance. International Journal of Obesity 23, S4–S11.CrossRefGoogle ScholarPubMed
Brun, S, Carmona, MC, Mampel, T, Vinas, O, Giralt, M, Iglesias, R & Villarroya, F (1999) Uncoupling protein-3 gene expression in skeletal muscle during development is regulated by nutritional factors that alter circulating non-esterified fatty acids. FEBS Letters 453, 205–209.CrossRefGoogle ScholarPubMed
Cadenas, S, Buckingham, JA, Samec, S, Seydoux, J, Din, N, Dulloo, AG & Brand, MD (1999) UCP2 and UCP3 rise in starved rat skeletal muscle but not mitochondrial proton conductance is unchanged. FEBS Letters 462, 257–260.CrossRefGoogle Scholar
Clapham, JC, Arch, JR, Chapman, A, Haynes, A, Lister, C, Moore, GBT, Piercy, V, Carter, SA, Lehner, I, Smith, SA, Beeley, LJ, Godden, RJ, Herrity, N, Skehel, M & Changani, KK (2000) Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature 406, 415–418.CrossRefGoogle ScholarPubMed
Cline, GW, Vidal-Puig, AJ, Dufour, S, Cadman, KS, Lowell, BB & Shulman, GI (2001) In vivo effects of uncoupling protein 3 gene disruption on mitochondrial metabolism. Journal of Biological Chemistry 276, 20240–20244.Google Scholar
Cortez-Pinto, H, Lin, HZ, Yang, SQ, Da Costa, SO & Diehl, AM (1999) Lipids up-regulate uncoupling protein 2 expression in rat hepatocytes. Gastroenterology 116, 1184–1193.CrossRefGoogle ScholarPubMed
Denjean, F, Lachuer, J, Geloen, A, Cohen-Adad, F, Moulin, C, Barre, H & Duchamp, C (1999) Differential regulation of uncoupling protein-1, -2 and -3 gene expression by sympathetic innervation in brown adipose tissue of thermoneutral or cold-exposed rats. FEBS Letters 444, 181–185.CrossRefGoogle ScholarPubMed
Diano, S, Urbanski, HF, Horvath, B, Bechmann, I, Kagiya, A, Nemeth, G, Naftolin, F, Warden, CH & Horvath, TL (2000) Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. Endocrinology 141, 4226–4238.CrossRefGoogle Scholar
Dulloo, AG (1999) UCP2 and UCP3: candidate genes for thermogenesis or lipid handling. Obesity Matters 2, 5–8.Google Scholar
Dulloo, AG & Girardier, L (1990) Adaptive changes in energy expenditure during refeeding following low calorie intake: evidence for a specific metabolic component favoring fat storage. American Journal of Clinical Nutrition 52, 415–420.CrossRefGoogle ScholarPubMed
Dulloo, AG & Girardier, L (1992) Influence of dietary composition on energy expenditure during recovery of body weight in the rat: Implications for catch-up growth and obesity relapse. Metabolism 41, 1336–1342.CrossRefGoogle ScholarPubMed
Dulloo, AG & Jacquet, J (1998) Adaptive reduction in basal metabolic rate in response to food deprivation in humans: a role for feedback signals from fat stores. American Journal of Clinical Nutrition 68, 599–606.CrossRefGoogle ScholarPubMed
Dulloo, AG & Jacquet, J (1999) Low-protein overfeeding: a tool to unmask susceptibility to obesity in humans. International Journal of Obesity 23, 1118–1121.Google Scholar
Dulloo, AG & Jacquet, J (2001) An adipose-specific control of thermogenesis in body weight regulation. International Journal of Obesity (In the Press).Google Scholar
Dulloo, AG & Miller, DS (1984) Energy balance following sympathetic denervation of brown adipose tissue. Canadian Journal of Physiology and Pharmacology 62, 235–240.CrossRefGoogle ScholarPubMed
Dulloo, AG & Miller, DS (1987) Obesity: a disorder of the sympathetic nervous system. World Reviews in Nutrition and Dietetics 50, 1–56.CrossRefGoogle ScholarPubMed
Dulloo, AG & Samec, S (2000) Uncoupling proteins: Do they have a role in weight regulation? News in Physiological Science 15, 313–318.Google ScholarPubMed
Dulloo, AG, Seydoux, J & Girardier, L (1995) Dissociation of enhanced efficiency of fat deposition during weight recovery from sympathetic control of thermogenesis. American Journal of Physiology 269, R365–R369.Google ScholarPubMed
Dulloo, AG, Jacquet, J & Girardier, L (1996) Autoregulation of body composition during weight recovery in humans: the Minnesota Experiment revisited. International Journal of Obesity 20, 393–405.Google ScholarPubMed
Enerbäck, S, Jacobsson, A, Simpson, EM, Guerra, C, Yamashita, H, Harper, ME & Kozak, LP (1997) Mice lacking mitochondrial uncoupling protein are cold sensitive but not obese. Nature 387, 90–94.CrossRefGoogle Scholar
Fleury, C, Neverova, M, Collins, S, Raimbault, S, Champigny, O, Levi-Meyrueis, C, Bouillaud, F, Seldin, MF, Surwit, RS, Ricquier, D & Warden, CH (1997) Uncoupling protein-2: A novel gene linked to obesity and hyperinsulinaemia. Nature and Genetics 15, 269–272.Google Scholar
Garlid, KD, Orosz, DE, Modriansky, M, Vassanelli, S & Jezek, P (1996) On the mechanism of fatty acid-induced proton transport by mitochondrial protein. Journal of Biological Chemistry 271, 2615–2620.CrossRefGoogle Scholar
Girardier, L (1983) Brown fat: an energy dissipating tissue. In Mammalian Thermogenesis, pp. 51–97 [Girardier, L and Stock, MJ, editors]. London: Chapman & Hall.CrossRefGoogle Scholar
Gong, DW, He, Y, Karas, M & Reitman, ML (1997) Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, β-adrenergic agonists, and leptin. Journal of Biological Chemistry 272, 24129–24132.Google Scholar
Gong, DW, Monemdjou, S, Gavrilova, O, Leon, LR, Marcus-Samuels, B, Chou, CJ, Everett, C, Kozak, LP, Li, C, Deng, C, Harper, ME & Reitman, ML (2000) Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. Journal of Biological Chemistry 275, 16251–16257.CrossRefGoogle ScholarPubMed
Harper, ME & Himms-Hagen, J (2001) Mitochondrial efficiency: lessons learned from transgenic mice. Biochimica et Biophysica Acta 1504, 159–172.CrossRefGoogle ScholarPubMed
Hildebrandt, AL & Neufer, DL (2000) Exercise attenuates the fasting-induced transcriptional activation of metabolic genes in skeletal muscle. American Journal of Physiology 278, E1078–E1086.Google ScholarPubMed
Himms-Hagen, J (1989) Brown adipose tissue thermogenesis and obesity. Progress in Lipid Research 28, 67–115.CrossRefGoogle ScholarPubMed
Himms-Hagen, J & Harper, ME (2001) Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Proceedings of the Society for Experimental Biology and Medicine 226, 78–84.CrossRefGoogle ScholarPubMed
Hjeltnes, N, Fernström, M, Zierath, JR & Krook, A (1999) Regulation of UCP2 and UCP3 by muscle disuse and physical activity in tetraplegic subjects. Diabetologia 42, 826–830.CrossRefGoogle ScholarPubMed
Iossa, S, Lionetti, L, Mollica, MP, Crescenzo, R, Barletta, A & Liverini, G (2000) Effect of long-term high-fat feeding on energy balance and liver oxidative activity in rats. British Journal of Nutrition 84, 377–385.Google Scholar
Jansky, L (1995) Humoral thermogenesis and its role in maintaining energy balance. Physiology Review 75, 237–259.CrossRefGoogle ScholarPubMed
Jezek, P, Engstova, H, Zackova, M, Vercesi, AE, Costa, AD, Arruda, P & Garlid, KD (1998) Fatty acid cycling mechanism and mitochondrial uncoupling proteins. Biochimica et Biophysica Acta 1365, 319–327.Google Scholar
Jucker, BM, Ren, J, Dufour, S, Cao, X, Previs, SF, Cadman, KS & Schulman, GI (2000) 13C/31P NMR assessment of mitochondrial energy coupling in skeletal muscle of awake fed and fasted rats: relationship with uncoupling protein 3 expression. Journal of Biological Chemistry 275, 39279–39286.Google Scholar
Keys, A, Brozek, J, Henschel, A, Mickelson, O & Taylor, HL (1950) The Biology of Human Starvation.Minneapolis, MN: University of Minnesota Press.CrossRefGoogle Scholar
Kozak, LP & Harper, ME (2000) Mitochondrial uncoupling proteins in energy expenditure. Annual Review of Nutrition 20, 339–363.CrossRefGoogle ScholarPubMed
Landsberg, L, Saville, ME & Young, JB (1984) The sympathoadrenal system and regulation of thermogenesis. American Journal of Physiology 247, E181–E189.Google ScholarPubMed
Lavoisier, AL & Laplace, PS (1780) Mémoire sur la Chaleur (Review on Heat Production); Oeuvres de Lavoisier, Paris: L'Academie Royale.Google Scholar
Lean, ME (1989) Brown adipose tissue in humans. Proceedings of the Nutrition Society 48, 243–256.CrossRefGoogle ScholarPubMed
Lean, ME, James, WP, Jennings, G & Trayhurn, P (1986) Brown adipose tissue in patients with phaeochromocytoma. International Journal of Obesity 10, 219–227.Google ScholarPubMed
Leibel, RL, Rosenbaum, M & Hirsch, J (1995) Changes in energy expenditure resulting from altered body weight. New England Journal of Medicine 332, 621–628.Google Scholar
Levine, JA, Eberhardt, NL & Jensen, MD (1999) Role of non-exercise activity thermogenesis in resistance to fat gain in humans. Science 283, 212–214.CrossRefGoogle Scholar
Luke, A & Schoeller, D (1992) Basal metabolic rate, fat-free-mass, and body cell mass during energy restriction. Metabolism 41, 450–456.Google Scholar
Ma, SWY & Foster, DO (1986) Starvation-induced changes in metabolic rate, blood flow, and regional energy expenditure in rats. Canadian Journal of Physiology and Pharmacology 64, 1252–1258.Google Scholar
Ma, SWY, Nadeau, BE & Foster, DO (1987) Evidence for liver as the major site of the diet-induced thermogenesis of rats fed a cafeteria-diet. Canadian Journal of Physiology and Pharmacology 65, 1802–1804.CrossRefGoogle ScholarPubMed
Mao, W, Yu, XX, Zhong, A, Li, W, Brush, J, Sherwood, SW, Adams, SH & Pan, G (1999) UCP4, a novel brain-specific mitochondrial protein that reduces membrane potential in mammalian cells. FEBS Letters 443, 326–330.CrossRefGoogle ScholarPubMed
Matthias, A, Kerstin, BE, Ohlson, BE, Fredriksson, JM, Jacobsson, A, Nedergaard, J & Cannon, B (2000) Thermogenic responses in brown fat cells are fully UCP1-dependent. Journal of Biological Chemistry 33, 25073–25081.CrossRefGoogle Scholar
Miller, DS (1982) Factors affecting energy expenditure. Proceedings of the Nutrition Society 41, 193–202.CrossRefGoogle ScholarPubMed
Miller, DS & Mumford, P (1967) Gluttony 1. An experimental study of overeating low- or high-protein diets. American Journal of Clinical Nutrition 20, 1212–1222.Google Scholar
Miller, DS, Mumford, P & Stock, MJ (1967) Gluttony 2. Thermogenesis in overeating man. American Journal of Clinical Nutrition 20, 1223–1229.CrossRefGoogle ScholarPubMed
Millet, L, Vidal, H, Andreelli, F, Larrouy, D, Riou, JP, Ricquier, D, Laville, M & Langin, D (1997) Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans. Journal of Clinical Investigation 100, 2665–2670.CrossRefGoogle ScholarPubMed
Monemdjou, S, Hofmann, WE, Kozak, LP & Harper, ME (2000) Increased mitochondrial proton leak in skeletal muscle mitochondria of UCP1-deficient mice. American Journal of Physiology E941–E946.Google ScholarPubMed
Muoio, D, Vidal-Puig, AJ, Grujic, D, Koves, T, Dohm, GL, Lowell, B, Cortright, R, LGirardier, & MJStock, (2000) Fuel metabolism in muscles from UCP-3 knock-out mice. Keystone Symposium on Molecular Control of Adipogenesis and Obesity, Silverthorne, Colorado, USA, p. 143.Google Scholar
Nagase, I, Yoshida, T, Kumamoto, K, Umekawa, T, Sakane, N, Nikami, H, Kawada, T & Saito, M (1996) Expression of uncoupling protein in skeletal muscle and white adipose tissue of obese mice treated with thermogenic β3-adrenergic agonist. Journal of Clinical Investigation 97, 2898–2904.CrossRefGoogle Scholar
Nedergaard, J & Cannon, B (1992) The uncoupling protein thermogenin and mitochondrial thermogenesis. In New Comprehensive Biochemistry (Molecular Mechanisms in Bioenergetics) pp. 385–419 [Ernster, L, editor]. Amsterdam: Elsevier Science Publishers.Google Scholar
Négre-Salvayre, A, Hirtz, C, Carrera, G, Cazenave, R, Troly, M, Salvayre, R, Penicaud, L & Casteilla, L (1997) A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB Journal 11, 809–815.CrossRefGoogle ScholarPubMed
Nicholls, DG & Rial, E (1999) A history of the first uncoupling protein, UCP1. Journal of Bioenergetics and Biomembranes 31, 399–406.CrossRefGoogle ScholarPubMed
Pastore, D, Fratianni, A, Di Pede, S & Passarella, S (2000) Effects of fatty acids, nucleotides and reactive oxygen species on durum wheat mitochondria. FEBS Letters 470, 88–92.Google Scholar
Peachey, T, French, RR & York, DA (1988) Regulation of GDP binding and uncoupling protein concentration in brown adipose tissue mitochondria. Biochemistry Journal 249, 451–457.Google Scholar
Pecqueur, C, Alves-Guerra, MC, Gelly, C, Lévi-Meyrueis, C, Couplan, E, Collins, S, Ricquier, D, Bouillaud, F & Miroux, B (2001a) Uncoupling protein 2: in vivo distribution, induction upon oxidative stress and evidence for translational regulation. Journal of Biological Chemistry 276, 8705–8712.CrossRefGoogle ScholarPubMed
Pecqueur, C, Couplan, E, Bouillaud, F & Ricquier, D (2001b) Genetic and physiological analysis of the role of uncoupling proteins in human energy homeostasis. Journal of Molecular Medicine 79, 48–56.Google Scholar
Raimbault, S, Dridi, S, Denjean, F, Lachuer, J, Couplan, E, Bouillaud, F, Bordas, A, Duchamp, C, Taouis, M & Ricquier, D (2001) An uncoupling protein homologue putatively involved in facultative muscle thermogenesis in birds. Biochemistry Journal 353, 441–444.CrossRefGoogle ScholarPubMed
Rashid, A, Wu, TC, Huang, CC, Chen, CH, Lin, HZ, Yang, SQ, Lee, FY & Diehl, AM (1999) Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver. Hepatology 29, 1131–1138.CrossRefGoogle ScholarPubMed
Richard, D, Huang, Q, Sanchis, D & Ricquier, D (1999) Brain distribution of UCP2 mRNA: in situ hybridization histochemistry studies. International Journal of Obesity 23 Suppl. 6, S53–S55.Google Scholar
Ricquier, D & (1999) The family of uncoupling proteins and its role in energy expenditure and body weight control. In Progress in Obesity Research: 8, pp. 381–385 [Guy-Grand, B and Ailhaud, G, editors]. London: John Libbey.Google Scholar
Ricquier, D & Bouillaud, F (2000) The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochemical Journal 345, 161–179.Google Scholar
Rolfe, DF & Brand, MD (1996) Contribution of mitochondrial proton leak to skeletal muscle respiration and to standard metabolic rate. American Journal of Physiology 271, 1380–1389.CrossRefGoogle ScholarPubMed
Rothwell, NJ & Stock, MJ (1979) A role for brown adipose tissue in diet-induced thermogenesis. Nature 281, 31–35.CrossRefGoogle ScholarPubMed
Samec, S, Seydoux, J & Dulloo, AG (1998a) Role of UCP homologues in skeletal muscles and brown adipose tissue: mediators of thermogenesis or regulators of lipids as fuel substrate? FASEB Journal 12, 715–724.Google Scholar
Samec, S, Seydoux, J & Dulloo, AG (1998b) Interorgan signaling between brown adipose tissue metabolism and skeletal muscle uncoupling protein homologs: Is there a role for circulating free fatty acids? Diabetes 47, 1693–1698.CrossRefGoogle Scholar
Samec, S, Seydoux, J & Dulloo, AG (1999) Post-starvation gene expression of skeletal muscle uncoupling protein 2 and uncoupling protein 3 in response to dietary fat levels and fatty acid composition. A link with insulin resistance. Diabetes 48, 436–441.CrossRefGoogle ScholarPubMed
Samec, S, Seydoux, J & Dulloo, AG (2000a) Further dissociations between skeletal muscle UCPs gene expressions and dietary regulation of thermogenesis. International Journal of Obesity 24 Suppl. 1, S61.Google Scholar
Samec, S, Seydoux, J & Dulloo, AG (2000b) Downregulation of skeletal muscle UCP-3 gene expression during refeeding is prevented by cold exposure. European Journal of Physiology 439, 723–729.Google Scholar
Samec, S, Seydoux, J & Dulloo, AG (2001) Skeletal muscle heterogeneity in fasting-induced upregulation of genes encoding UCP2, UCP3 and key regulators of lipid oxidation. International Journal of Obesity 25 Suppl. 2, S49.Google Scholar
Sanchis, D, Fleury, C, Chomiki, N, Goubern, M, Huang, Q, Neverova, M, Gregoire, F, Easlick, J, Raimbault, S, Levi-Meyrueis, C, Miroux, B, Collins, S, Seldin, M, Richard, D, Warden, C, Bouillaud, F & Ricquier, D (1998) BMCP1, a novel mitochondrial carrier with high expression in the central nervous system of humans and rodents, and respiration uncoupling activity in recombinant yeast. Journal of Biological Chemistry 273, 34611–34615.CrossRefGoogle ScholarPubMed
Schrauwen, P, Hoppeler, H, Billeter, R, Bakker, AHF & Pendergast, DR (2001) Fiber type dependent upregulation of human skeletal muscle UCP2 and UCP3 mRNA expression by high-fat diet. International Journal of Obesity 25, 449–456.Google Scholar
Simoneau, JA, Kelley, DE, Neverova, M & Warden, CH (1998) Overexpression of muscle uncoupling protein-2 in human obesity associated with reduced muscle lipid utilization. FASEB Journal 12, 1739–1745.CrossRefGoogle ScholarPubMed
Skulachev, VP (1996) Role of uncoupled and non-coupled oxidations in maintenance of safely low levels of oxygen and its one-electron reductants. Quarterly Review of Biophysics 29, 169–202.Google Scholar
Skulachev, VP (1998) Uncoupling: new approaches to an old problem of bioenergetics. Biochimica et Biophysica Acta 1363, 100–124.CrossRefGoogle Scholar
Stock, MJ (1999a) Gluttony and thermogenesis revisited. International Journal of Obesity 23, 1105–1117.Google Scholar
Stock, MJ (1999b) Molecular and genetic aspects of the UCPs: view from the chair. International Journal of Obesity 23 Suppl. 6, S51–S52.Google Scholar
Steppan, CM, Bailey, ST, Bhat, S, Brown, EJ, Banerjee, RR, Wright, CM, Patel, HR, Ahima, RS & Lazar, MA (2001a) The hormone resistin links obesity to diabetes. Nature 409, 307–312.Google Scholar
Stuart, JA, Cadenas, S, Jekabsons, MB, Roussel, D & Brand, MD (2001b) Mitochondrial proton leak and the uncoupling protein 1 homologues. Biochimca et Biophysica Acta 1504, 144–158.Google Scholar
Stuart, JA, Harper, JA, Brindle, KM, Jekabsons, MB & Brand, MD (2001) Physiological levels of mammalian uncoupling protein 2 do not uncouple yeast mitochondria. Journal of Biological Chemistry 276, 18633–18639.CrossRefGoogle Scholar
Trayhurn, P (1990) Energy expenditure and thermogenesis: animal studies on brown adipose tissue. International Journal of Obesity 14 Suppl. 1, 17–26.Google Scholar
Van der Lee, KAJM, Willemsen, PHM, Van der Vusse, GJ & Van Bilsen, M (2000) Effects of fatty acids on uncoupling protein-2 expression in the rat heart. FASEB Journal 14, 495–502.Google Scholar
Vianna, CR, Hagen, T, Zhang, CY, Bachman, E, Boss, O, Gereben, B, Moriscot, AS, Lowell, BB, Bicudo, JE & Bianco, AC (2001) Cloning and functional characterization of an uncoupling protein homolog in hummingbirds. Physiology and Genomics 5, 137–145.CrossRefGoogle ScholarPubMed
Vidal-Puig, AJ, Solanes, G, Grujic, D, Flier, JS & Lowell, BB (1997) An uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochemistry and Biophysics Research Communications 235, 79–82.CrossRefGoogle ScholarPubMed
Vidal-Puig, AJ, Grujic, D, Zhang, CY, Hagen, T, Boss, O, Ido, Y, Szczepanik, A, Wade, J, Mootha, V, Cortright, R, Muoio, DM & Lowell, BB (2000) Energy metabolism in uncoupling protein 3 gene knockout mice. Journal of Biological Chemistry 275, 16258–16266.CrossRefGoogle ScholarPubMed
Weigle, DS, Selfridge, LE, Schwartz, MW, Seeley, RJ, Cummings, DE, Havel, PJ, Kuijper, JL and Bertrande Rio, H (1998) Elevated free fatty acids induce uncoupling protein 3 expression in muscle. A potential explanation for the effect of fasting. Diabetes 47, 298–302.Google Scholar
Weyer, C, Gauthier, JF & Danforth, E (1999) Development of beta 3-adrenoceptor agonists for the treatment of obesity and diabetes - an update. Diabetes Metabolism 25, 11–21.Google Scholar
Weyer, C, Walford, RL, Harper, IT, Milner, M, MacCallum, T, Tataranni, PA & Ravussin, E (2000) Energy metabolism after 2 yr of energy restriction: the Biosphere 2 experiment. American Journal of Clinical Nutrition 72, 946–953.CrossRefGoogle Scholar
Williams, RS & Wagner, PD (2000) Transgenic animals in integrative biology: approaches and interpretations of outcome. Journal of Applied Physiology 88, 1119–1126.CrossRefGoogle ScholarPubMed
Yu, XX, Mao, W, Zhong, A, Schow, P, Brush, J, Sherwood, SS, Adams, SH & Pan, G (2000) Characterization of novel UCP5/BMCP1 isoforms and differential regulation of UCP4 and UCP5 expression through dietary or temperature manipulation. FASEB Journal 14, 1611–1618.CrossRefGoogle ScholarPubMed