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. 2011 Dec 28:2:85.
doi: 10.3389/fendo.2011.00085. eCollection 2011.

Uncoupling protein 1 of brown adipocytes, the only uncoupler: a historical perspective

Daniel Ricquier  1
Affiliations

Uncoupling protein 1 of brown adipocytes, the only uncoupler: a historical perspective

Daniel Ricquier. Front Endocrinol (Lausanne). .

Abstract

Uncoupling protein 1 (UCP1), is a unique mitochondrial membranous protein devoted to adaptive thermogenesis, a specialized function performed by brown adipocytes. Whereas the family of mitochondrial metabolite carriers comprises ∼40 members, UCP1 is the only memberable to translocate protons through the inner membrane of brown adipocyte mitochondria. By this process, UCP1 uncouples respiration from ATP synthesis and therefore provokes energy dissipation in the form of heat while, also stimulating high levels of fatty acid oxidation. UCP1 homologs were identified but they are biochemically and physiologically different from UCP1. Thirty five years after its identification, UCP1 still appears as a fascinating component. The recent renewal of the interest in human brown adipose tissue makes UCP1 as a potential target for strategies of treatment of metabolic disorders.

Keywords: brown adipocyte; fatty acid; membranous carrier; mitochondria; proton transport; respiration coupling; thermogenesis; uncoupling.

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Figures

Figure 1
Figure 1
Histology of brown adipocyte and presence of UCP1 in mitochondria. The cytosol of brown adipocytes is characterized by numerous mitochondria and lipid droplets (upper part). Magnification of a brown adipocyte mitochondrion showing parallel cristae and UCP1 detected using antibodies (black dots, lower part). (Figure kindly provided by Dr. Saverio Cinti, University of Ancona).
Figure 2
Figure 2
Proton circuit. UCP1 is inserted in the mitochondrial inner membrane where, also present, is a multienzymatic complex called the respiratory chain made of complexes I to IV. The respiratory chain reoxidizes reduced coenzymes and electrons are driven to oxygen. This oxido-reduction step liberates energy which is used to generate an electrochemical gradient of protons across the inner membrane. This gradient is normally consumed by the ATP-synthase which phosphorylates ADP. UCP1 transports protons passively and makes possible a futile cycle of protons across the inner membrane leading to increased energy expenditure. This schema illustrates the situation encountered in brown adipocytes of mammals where a large amount of respiratory chains as well as a large amount of UCP1 are present. Activation of the futile cycling increases considerably energy expenditure and thus heat production by these thermogenic cells. In other cells where homologs of the UCP1 are expressed at much lower level, this pathway would represent a minor contributor to energy expenditure, but might be of importance to avoid oxidative damage (Figure kindly designed by Frédéric Bouillaud).
Figure 3
Figure 3
Reconstitution of the proton transport activity of purified UCP1 in liposomes (Mozo et al., 2006). Membrane potential (ΔΨ) is appreciated using a safranin probe sensitive to membrane potential and allowing a measurement of optical density at 520 nm. In presence of nigericin, H+ is exchanged against K+ (H+ in, K+ out), there is no charge exchange but a ΔpH is generated. In liposomes containing UCP1, UCP1 dissipates this ΔpH gradient and also increases ΔΨ inducing the polarization of the membrane (and a decrease of O.D. signal). The slope of the decrease of the safranin signal is an assay of UCP1 protonophoric activity. Addition of fatty acids to liposome containing UCP1 markedly polarizes the membrane due to activation of the protonophoric activity of UCP1. Upon addition of CCCP, a strong protonophor, H+ ions go out and positively polarize the liposome membrane on external side.
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