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Uncoupling Protein 1 of Brown Adipocytes, the Only Uncoupler: a Historical Perspective

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Uncoupling Protein 1 of Brown Adipocytes, the Only Uncoupler: a Historical Perspective View metadata, citation and similar papers at core.ac.uk brought to you by CORE MINI REVIEW ARTICLE published: 28 Decemberprovided 2011 by Frontiers - Publisher Connector doi: 10.3389/fendo.2011.00085 Uncoupling protein 1 of brown adipocytes, the only uncoupler: a historical perspective Daniel Ricquier* Institute Cochin, Paris Descartes University, Paris, France Edited by: Uncoupling protein 1 (UCP1), is a unique mitochondrial membranous protein devoted to Patrick Seale, University of adaptive thermogenesis, a specialized function performed by brown adipocytes. Whereas Pennsylvania, USA the family of mitochondrial metabolite carriers comprises ∼40 members, UCP1 is the only Reviewed by: Marta Letizia Hribal, University of memberable to translocate protons through the inner membrane of brown adipocyte mito- Catanzaro Magna Graecia, Italy chondria. By this process, UCP1 uncouples respiration from ATP synthesis and therefore Carol Huang, University of Calgary, provokes energy dissipation in the form of heat while, also stimulating high levels of fatty Canada acid oxidation. UCP1 homologs were identified but they are biochemically and physiolog- *Correspondence: ically different from UCP1.Thirty five years after its identification, UCP1 still appears as a Daniel Ricquier, Paris Descartes, Institute Cochin, 24 Rue du Faubourg fascinating component. The recent renewal of the interest in human brown adipose tissue Saint-Jacques, 75014 Paris Cedex, makes UCP1 as a potential target for strategies of treatment of metabolic disorders. France. Keywords: brown adipocyte, fatty acid, membranous carrier, mitochondria, proton transport, respiration coupling, e-mail: daniel.ricquier@ thermogenesis, uncoupling parisdescartes.fr INTRODUCTION since they contain an extremely high number of mitochondria; FROM PHYSIOLOGICAL MEASUREMENTS OF THERMOGENESIS TO THE these specialized mitochondria have a highly developed inner IDENTIFICATION OF UCP1 membrane, the membrane where the respiratory chain complexes Basal thermogenesis results from the basal activity of many bio- are anchored. In other words,the morphology of brown adipocytes chemical pathways including ATP-ases and futile cycles. Adaptive confers on these cells a very high capacity to oxidize substrates thermogenesis is regulated and occurs in particular conditions (Figure 1). Therefore, when heat is required (exposure to the (cold exposure, arousing from hibernation, food intake...). This cold, as an example), norepinephrine released by sympathetic process involves the recruitment of different cell types and the acti- nerves rapidly activates brown adipocytes resulting in fatty acid vation of specific biochemical pathways. Any process that occurs oxidation and heat production. Independently, Smith and Lind- without performing useful work, accumulating intermediates, or berg observed in 1967 that thermogenesis in brown adipose cells concentrating ions has an efficiency of zero from the standpoint resulted from a weak coupling of respiration to ADP phosphoryla- of energy conservation or 100% for the purposes of thermogene- tion, leading to waste of oxidation energy as heat. Some years later, sis (Nicholls and Locke, 1984). Although ATP-ases contribute, the Nicholls and Ricquier showed the presence of a specific 32-kD pro- largest part of heat production by cells probably comes from many tein in the inner mitochondrial membrane of brown adipocytes metabolic pathways and in particular from oxidation of substrates. (Figure 1) that could uncouple respiration to produce heat rather In rodents or in newborns of some species, elegant in vivo stud- than ATP (see reviews in Nicholls and Locke, 1984; Cannon and ies in the 1960s established that brown fat depots were engaged Nedergaard, 2004; Nedergaard et al., 2005). This protein was later in thermogenesis; this led to an increase in the temperature of termed uncoupling protein UCP and renamed uncoupling pro- the blood in brown fat which was rapidly distributed to heart, tein 1 (UCP1) when UCP2 was identified (Fleury et al., 1997). The brain, kidney, and skeletal muscle (reviews in Nicholls and Locke, obvious thermogenic activity of UCP1 in mitochondria was clearly 1984; Cannon and Nedergaard, 1985, 2004; Himms-Hagen and demonstrated by Kozak et al. (1994) observing the cold sensitive Ricquier, 1998). The thermogenic activity of brown adipocytes phenotype of the Ucp1−/− mouse (Enerbäck et al., 1997). UCP1 was confirmed by microcalorimetric determinations of the heat activity and regulation are reviewed below. output of excised tissue, isolated brown adipocytes, and isolated brown fat mitochondria (Nedergaard et al., 1977; Seydoux and UCP1: A SPECIFIC PROTON CARRIER UNCOUPLING Girardier, 1977; Ricquier et al., 1979). Physiological or pharmaco- RESPIRATION FROM ATP SYNTHESIS logical experiments established that the ability of animals (mainly UCP1 IS A RESPIRATION UNCOUPLER, SHUNTING THE NORMAL rodents) to activate thermogenesis in response to cold exposure PROTON CIRCUIT AND IS PHYSIOLOGICALLY REGULATED correlates with the amount of brown fat and to its activation by The physiological measurements of BAT thermogenic activity the sympathetic nervous system mediates and (Himms-Hagen, instigated the search for a mechanism unique to brown adipocyte 1989). mitochondria. The search for a respiration uncoupling mecha- Thermogenesis is dependent on oxygen consumption and nism, unique to these mitochondria came at a moment when therefore on the ability of cells to oxidize substrates in their Mitchell had proposed the – rather debated at that time – chemi- mitochondria. Morphologically,brown adipocytes are very unique osmotic theory; a theory explaining that the proton gradient and www.frontiersin.org December 2011 | Volume 2 | Article 85 | 1 Ricquier UCP1 that oxygen consumption and ATP synthesis were tightly linked (Figure 2). Consequently, a proton leak in the inner mitochondrial membrane,distinct from the re-entry of protons via ATP-synthase, would lower the proton gradient and allow energy to be dissipated as heat. The reason for that is that down regulation of the pro- ton gradient lowers the membrane potential which immediately activates the proton pumps and respiratory chain and provokes heat production since oxidation energy is not consumed by the ATP-synthase machinery. Actually, this is what happens when a chemical uncoupler is added to respiring liver or skeletal muscle mitochondria. Taken into consideration this postulate, Nicholls observed that isolated brown adipocyte mitochondria exhibit a very high and unique ion permeability in their inner membrane (review in Nicholls, 2006). This ion permeability, first detected as a chloride permeability, is a proton permeability strongly inhib- ited in presence of nucleotides, previously shown by Rafael and others to restore the respiratory control of brown adipocyte mito- chondria (reviews in Cannon and Nedergaard, 2004; Nicholls, 2006). Photo-affinity labeling of hamster brown fat mitochon- dria with radioactive nucleotides was used by Heaton et al. (1978) to identify the uncoupling (proton transport) pathway as a 32- kD membranous protein. These data were in agreement with the previous description of this protein, when such a protein was (i) described to be present in rat brown fat mitochondria membrane but absent in liver mitochondria, (ii) the only membrane protein to be significantly increased in brown fat mitochondria following cold-adaptation, and (iii), down regulated when cold-exposed ani- mals returned to the warm (Ricquier and Kader, 1976). Therefore, UCP1 not only plays an important physiological role in Nature, it also occupies a unique position among the family of membranous mitochondrial porters driven by oxidative metabolism: it is the exception that proves the rule of chemi-osmotic theory (Garlid and Jaburek, 1998; Figure 2). UCP1 PROTON TRANSPORT ACTIVITY AND REGULATION FIGURE 1 | Histology of brown adipocyte and presence of UCP1 in Nicholls developed a methodology to determine the cur- mitochondria. The cytosol of brown adipocytes is characterized by rent/voltage relationship of the basal proton leak of mitochondria numerous mitochondria and lipid droplets (upper part). Magnification of a by titrating down succinate respiration with malonate, allowing brown adipocyte mitochondrion showing parallel cristae and UCP1 + detected using antibodies (black dots, lower part). (Figure kindly provided to calculate CmH , the proton conductance of the inner mem- + − − − by Dr. Saverio Cinti, University of Ancona). brane of liver mitochondria in nanomole H /min 1/mg 1,mv 1. Doing that with brown fat mitochondria, he found that the freshly prepared mitochondria had an enormous proton conductance and proton circuit through the inner membrane of mitochondria or were incapable to maintain more than a few mV of proton-motive chloroplasts, were governing ADP phosphorylation following res- force whereas coupled mitochondria exhibit a membrane poten- piration or exposure to light. According to Mitchell, oxidative tial value close to 200 mV. It became clear that UCP1, when active, phosphorylation is the process by which ADP phosphorylation was acting as a proton translocator (Nicholls, 2006). When ther- by the mitochondrial ATP-synthase is coupled to mitochondrial mogenesis is not required, nucleotides bind UCP1 and inhibit oxygen consumption and to re-oxidation of reduced coenzymes its activity. In presence of inhibitory nucleotides, UCP1 has no via the proton electrochemical gradient generated by complexes residual proton
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