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PubMed2001

Gene expression of leptin and uncoupling proteins: molecular end-points of fetal development.

Uncoupling proteins (UCPs) are considered to be major determinants of energy expenditure in mammals. During development in rodents, the expression of the UCP genes occurs sequentially. UCP2 mRNA is expressed long before birth. UCP1 mRNA expression in brown adipose tissue (BAT) starts in the late fetal period, and the expression of UCP3 mRNA begins immediately after birth in BAT and skeletal muscle. The postnatal induction of UCP1 gene expression is due mainly to cold stimuli, whereas the switch-on of UCP3 mRNA expression after birth requires the stimulus of food intake, specifically of lipids in the mother's milk. However, UCP3 mRNA expression after birth is also highly sensitive to leptin, and administration of a single injection of leptin to neonatal mice that were not allowed to suckle partly mimicked the natural induction of UCP3 gene expression in BAT and skeletal muscle. The speed of the effects of leptin on UCP3 mRNA expression suggests a direct action on skeletal muscle and BAT. The injection of leptin produced minor effects on UCP1 mRNA expression, and no effects were observed on UCP2 mRNA. In summary, leptin appears to contribute to the regulation of UCP3 gene expression in the perinatal period. Whatever the mechanism of action of leptin in BAT and skeletal muscle, it is already functional at birth.

Adipose Tissue, Brown↗
PubMed2001

Perspectives on the biology of uncoupling protein (UCP) homologues.

In mammals, it is believed that a portion of tissue metabolic rate is driven by counteraction of uncoupling, in which the energetically inefficient process of proton leak acts to diminish the mitochondrial electrochemical membrane potential. It is proposed that specific proteins associated with the mitochondrion catalyse uncoupling, and the biology of such putative uncoupling proteins (UCPs) is the subject of active research efforts. UCP4 and UCP5 are interesting in light of their abundant expression in the brain, which may signal an important metabolic function in thermogenesis or regulation of reactive oxygen species in that tissue. While each is expressed to various degrees outside of the brain, their impact on whole-animal metabolism remains to be clarified further. Transgenic mice expressing murine UCP5(L), the long isoform of UCP5, using an inducible metallothionine promoter (to drive expression of the transgene in liver, testis, heart, lung, spleen, intestine, kidney and brain) did not display any overt metabolic phenotype, despite liver UCP5(L) mRNA expression equivalent to that of normal mouse brain. This highlights the need for further studies to examine the nature of UCP5 physiology. Evidence for uncoupling behaviour has recently emerged from studies of the human 2-oxoglutarate carrier (OGC), indicating that the possibility of physiological proton leak elicited by the OGC and other mitochondrial carriers warrants further experimental evaluation.

Animals↗
PubMed2001

Tissue-specific activity of lipoprotein lipase in skeletal muscle regulates the expression of uncoupling protein 3 in transgenic mouse models.

Uncoupling protein (UCP)-2 and UCP-3 are two recently discovered proteins similar to UCP-1, which regulates thermogenesis in brown adipose tissue (BAT). Whereas UCP-1 expression is restricted to BAT, UCP-2 is widely expressed. UCP-3 is found mainly in skeletal muscle and BAT. A large body of evidence exists that the expression of UCP-2 and UCP-3 in skeletal muscle of mice is regulated by feeding/fasting, and some studies have suggested that this effect might be caused by the changing concentration of plasma non-esterified fatty acids (NEFAs). In an attempt to determine whether the increased import of triacylglycerol-derived NEFAs can also affect UCP expression, we determined the mRNA levels of UCP-1, UCP-2 and UCP-3 in BAT and muscle of induced mutant mouse lines that overexpressed or lacked lipoprotein lipase (LPL) in these tissues. The expression levels of UCP-1 and UCP-2 in BAT and in skeletal and cardiac muscle respectively were not affected by variations in tissue LPL activities. In contrast, UCP-3 mRNA levels were induced 3.4-fold in mice with high levels of LPL in skeletal muscle, and down-regulated in mice that lacked LPL in skeletal muscle. The presence or absence of LPL in BAT had no effect on UCP-3 expression levels. The response of UCP-3 mRNA expression to variations in LPL activity in skeletal muscle was independent of the feeding status or of plasma NEFA concentrations. These findings indicated that NEFAs as lipolytic products of LPL-mediated triacylglycerol hydrolysis markedly affect UCP-3 expression and that increased LPL activities occurring during fasting in skeletal muscle contribute to the induction of UCP-3 expression by promoting the increased uptake of NEFAs. In addition, our results demonstrate that UCP-2 and UCP-3 are differentially regulated in response to LPL-mediated NEFA uptake in skeletal muscle of mice.

Adipose Tissue, Brown↗
PubMed2003

The role of uncoupling proteins in the regulation of metabolism.

Investigations of variations in metabolic efficiency and thermogenesis have a short and turbulent history. In small animals, non-shivering thermogenesis and diet-induced thermogenesis have a great impact on overall body weight, and the question is whether mechanisms to waste energy have evolved also in human energy metabolism. The candidate molecules for this adaptive thermogenesis are the uncoupling proteins. This is a newly discovered family of proteins, consisting of at least five proteins, namely UCP1, UCP2, UCP3, UCP4 and UCP5. Although a role for UCP1 in thermogenesis is unequivocal, the physiological function of the newer uncoupling proteins is as yet unclear. UCP1 is present in brown adipose tissue and has a well-documented role in cold-induced thermogenesis. The targeted disruption of the UCP1-gene rendered animals that were cold sensitive, but not obese. UCP2 mRNA has a ubiquitous distribution in tissue, namely, in skeletal muscle, white and brown adipose tissue, the gastro-intestinal tract, the lung and the spleen. By targeting the UCP2-gene there was no effect on whole body energy metabolism, but instead, a reduced ability to protect against free-radical oxygen species. UCP2 has also been shown to act as a negative regulator for insulin secretion. UCP3 is present in skeletal muscle. Targeted disruption of the UCP3-gene gave no effect on whole body energy metabolism, but showed the mitochondria in muscle to be more coupled. In conclusion, the uncoupling proteins may be important in various specific ways, as protectors of free radical oxygen species and as regulators of ATP-dependent processes.

Adenosine Triphosphate↗
PubMed1999

Contributions of studies on uncoupling proteins to research on metabolic diseases.

The coupling of O2 consumption to ADP phosphorylation in mitochondria is partial. This is particularly obvious in brown adipocyte mitochondria which use a regulated uncoupling mechanism generating heat production from substrate oxidation, and catalysing thermogenesis in rodents or infants in response to cold, and arousing hibernators. In the case of brown adipose tissue, the uncoupling mechanism is related to a specific protein in the inner mitochondrial membrane referred to as UCP1. Although the biological importance of UCP1 in human adults is not demonstrated, genetic analysis of various human cohorts suggested a participation of UCP1 to control of fat content and body weight. Very recently, the cloning of UCP2 and UCP3, two homologues of UCP1, has renewed the field of research on the importance of respiration control in metabolic processes and metabolic diseases. UCP2 is widely expressed in organs, whereas UCP3 is mainly present in muscles. These proteins may explain why the coupling of respiration to ADP phosphorylation is less than perfect. Their biological importance should be studied. They also represent new putative targets for drugs against metabolic diseases such as obesity.

Adipocytes↗
PubMed2000

The effects of rexinoids and rosiglitazone on body weight and uncoupling protein isoform expression in the Zucker fa/fa rat.

Agonists for the retinoid X receptor (RXR), the rexinoids, and the peroxisome proliferator-activated receptor gamma (PPARgamma), the thiazolidinediones, are effective in the treatment of insulin resistance in rodent models by enhancing insulin action and improving glycemic control. In the present study, we compared the effects of rexinoids and a thiazolidinedione on body weight and mitochondrial uncoupling protein (UCP) isoform mRNA expression in the obese Zucker fa/fa rat. Long-term (2 weeks) oral treatment with the rexinoids LG100268 and LG100324 reduced food intake and body weight gain, whereas rosiglitazone (BRL49653) tended to increase both food intake and weight gain. LG100268 and LG100324 increased brown adipose tissue (BAT) UCP-1 mRNA content by 2.7-fold (P < .002) and 3.1-fold (P < .001), respectively, while BRL49653 had no effect on BAT UCP-1 mRNA content. Neither the rexinoids nor the thiazolidinedione had any effect on the level of mRNA encoding UCP-2 and the recently described PPARgamma coactivator-1 (PGC-1). LG100324 increased UCP-3 mRNA content by 3.6-fold (P < .0005) in muscle and 4.3-fold (P < .0002) in white adipose tissue (WAT). LG100268 increased UCP-3 mRNA content in WAT by 2-fold (P < .005) but was without any effect on muscle UCP-3. BRL49653 increased UCP-3 mRNA content by 2.1-fold (P < .005) in muscle and 2.7-fold (P < .003) in WAT. Thus, the rexinoids, but not the thiazolidinedione, have an antiobesity action by reducing food intake, and the increase in UCP-1 mRNA content in BAT may reflect a stimulation of BAT UCP-1 activity.

Adipose Tissue, Brown↗
PubMed2000

Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty scid-induced thermogenesis.

To examine the thermogenic significance of the classical uncoupling protein-1 (UCP1), the thermogenic potential of brown adipocytes isolated from UCP1-ablated mice was investigated. Ucp1(-/-) cells had a basal metabolic rate identical to wild-type; the mitochondria within them were coupled to the same degree. The response to norepinephrine in wild-type cells was robust ( approximately 10-fold increase in thermogenesis); Ucp1(-/-) cells only responded approximately 3% of this. Ucp1(-/-) cells were as potent as wild-type in norepinephrine-induced cAMP accumulation and lipolysis and had a similar mitochondrial respiratory complement. In wild-type cells, fatty acids induced a thermogenic response similar to norepinephrine, but fatty acids (and retinoate) were practically without effect in Ucp1(-/-) cells. It is concluded that no other adrenergically induced thermogenic mechanism exists in brown adipocytes except that mediated by UCP1 and that entopic expression of UCP1 does not lead to overt innate uncoupling, and it is suggested that fatty acids are transformed to an intracellular physiological activator of UCP1. High expression of UCP2 and UCP3 in the tissue was not associated with an overt innate highly uncoupled state of mitochondria within the cells, nor with an ability of norepinephrine or endo- or exogenous fatty acids to induce uncoupled respiration in the cells. Thus, UCP1 remains the only physiologically potent thermogenic uncoupling protein in these cells.

Adipocytes↗
PubMed2001

UCP2-dependent proton leak in isolated mammalian mitochondria.

A role for uncoupling protein (UCP) homologues in mediating the proton leak in mammalian mitochondria is controversial. We subjected insulinoma (INS-1) cells to adenoviral expression of UCP2 or UCP1 and assessed the proton leak as the kinetic relationship between oxygen use and the inner mitochondrial membrane potential. Cells were infected with different amounts of rat UCP2, and, in other experiments, with either UCP2 or UCP1. The relative molar expression of these subtypes was quantified through comparison with histidine-tagged UCP1 or UCP2 proteins engineered by expression in Escherichia coli. Adenoviral infection with UCP2, compared with beta-galactosidase, resulted in a dose-dependent shift in kinetics indicating increased H(+) flux at any given membrane potential. UCP1 also enhanced H(+) flux, but, on a relative molar basis, the overexpression of the endogenous protein, UCP2, was more potent than UCP1. These results were not due to nonspecific overexpression of mitochondrial protein since UCP1 activity was inhibited by GDP and because overexpression of another membrane carrier protein, the oxoglutarate malate carrier had no effect. UCP2-mediated H(+) conduction was not GDP sensitive. These data suggest that the UCP homologue, UCP2, mediates the proton leak in mitochondria of a mammalian cell wherein UCP2 is the native subtype.

Animals↗
PubMed2002

Alteration of plant mitochondrial proton conductance by free fatty acids. Uncoupling protein involvement.

We characterized the uncoupling activity of the plant uncoupling protein from Solanum tuberosum (StUCP) using mitochondria from intact potato tubers or from yeast (Saccharomyces cerevisiae) expressing the StUCP gene. Compared with mitochondria from transfected yeast, StUCP is present at very low levels in intact potato mitochondrial membranes (at least thirty times lower) as shown by immunodetection with anti-UCP1 antibodies. Under conditions that ruled out undesirable effects of nucleotides and free fatty acids on uncoupling activity measurement in plant mitochondria, the linoleic acid-induced depolarization in potato mitochondria was insensitive to the nucleotides ATP, GTP, or GDP. In addition, sensitivity to linoleic acid was similar in potato and in control yeast mitochondria, suggesting that uncoupling occurring in potato mitochondria was because of a UCP-independent proton diffusion process. By contrast, yeast mitochondria expressing StUCP exhibited a higher sensitivity to free fatty acids than those from the control yeast and especially a marked proton conductance in the presence of low amounts of linoleic acid. However, this fatty acid-induced uncoupling was also insensitive to nucleotides. Altogether, these results suggest that uncoupling of oxidative phosphorylation and heat production cannot be the dominant feature of StUCP expressed in native potato tissues. However, it could play a role in preventing reactive oxygen species production as proposed for mammalian UCP2 and UCP3.

Carrier Proteins↗
PubMed2003

Reconstitution of recombinant uncoupling proteins: UCP1, -2, and -3 have similar affinities for ATP and are unaffected by coenzyme Q10.

The successful development of recombinant expression and reconstitution protocols has enabled a detailed study of the transport properties and regulation of the uncoupling proteins (UCP). We optimized conditions of isolation and refolding of bacterially expressed uncoupling proteins and reexamined the transport properties and regulation of bacterially expressed UCP1, -2, and -3 reconstituted in liposomes. We show for the first time that ATP inhibits UCP1, -2, and -3 with similar affinities. The Ki values for ATP inhibition were 50 microm (UCP1), 70 microm (UCP2), and 120 microm (UCP3) at pH 7.2. These affinities for ATP are similar to those obtained with native UCP1 isolated from brown adipose tissue mitochondria (Ki = 65 microm at pH 7.2). The Vmax values for proton transport were also similar among the UCPs, ranging from 8 to 20 micromol.min(-1).mg(-1), depending on experimental conditions. We also examined the effect of coenzyme Q on fatty acid-catalyzed proton flux in liposomes containing recombinant UCP1, -2, and -3. We found that coenzyme Q had no effect on the fatty acid-dependent proton transport catalyzed by any of the UCPs nor did it affect nucleotide regulation of the UCPs. We conclude that coenzyme Q is not a cofactor of UCP-mediated proton transport.

Adenosine Triphosphate↗
PubMed2000

Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3.

Uncoupling protein-3 (UCP3) is a mitochondrial protein that can diminish the mitochondrial membrane potential. Levels of muscle Ucp3 mRNA are increased by thyroid hormone and fasting. Ucp3 has been proposed to influence metabolic efficiency and is a candidate obesity gene. We have produced a Ucp3 knockout mouse to test these hypotheses. The Ucp3 (-/-) mice had no detectable immunoreactive UCP3 by Western blotting. In mitochondria from the knockout mice, proton leak was greatly reduced in muscle, minimally reduced in brown fat, and not reduced at all in liver. These data suggest that UCP3 accounts for much of the proton leak in skeletal muscle. Despite the lack of UCP3, no consistent phenotypic abnormality was observed. The knockout mice were not obese and had normal serum insulin, triglyceride, and leptin levels, with a tendency toward reduced free fatty acids and glucose. Knockout mice showed a normal circadian rhythm in body temperature and motor activity and had normal body temperature responses to fasting, stress, thyroid hormone, and cold exposure. The base-line metabolic rate and respiratory exchange ratio were the same in knockout and control mice, as were the effects of fasting, a beta3-adrenergic agonist (CL316243), and thyroid hormone on these parameters. The phenotype of Ucp1/Ucp3 double knockout mice was indistinguishable from Ucp1 single knockout mice. These data suggest that Ucp3 is not a major determinant of metabolic rate but, rather, has other functions.

Adipose Tissue, Brown↗
PubMed2000

Energy metabolism in uncoupling protein 3 gene knockout mice.

Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined.

Animals↗
PubMed2001

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

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.

Adipose Tissue↗
PubMed2002

Uncoupling proteins--a new family of proteins with unknown function.

Uncoupling proteins are inner mitochondrial membrane proteins, which dissipate the proton gradient, releasing the stored energy as heat. Five proteins have been cloned, named UCP1, UCP2, UCP3, UCP4 and UCP5/BMCP1. These proteins are structurally related but differ in tissue expression. UCP1 is expressed uniquely in the brown adipose tissue, while UCP2 is widely distributed, UCP3 is mainly restricted to skeletal muscle and UCP4 and UCP5/BMCP1 expressed in the brain. The properties and regulation of the uncoupling proteins and their exact function has been the focus of an intense research during recent years. This review briefly summarizes the actual knowledge of the properties and function of this new family of proteins. While UCP1 has a clear role in energy homeostasis, the newcomers UCP2-UCP5 may have more delicate physiological importance acting as free radical oxygen scavengers and in the regulation of ATP-dependent processes, such as secretion.

Animals↗
PubMed2000

Specific sequence of motifs of mitochondrial uncoupling proteins.

We have searched for the exclusivity of common sequence motifs of the mitochondrial uncoupling proteins (UCP1, UCP2, UCP3, UCP4, BMCP1, and plant UCP [PUMP]) within the gene family of mitochondrial anion carrier proteins. The UCP-specific sequences, "UCP signatures", were found in the first, second, and fourth alpha-helices. First: Ala/Ser-Cys/Thr/n-n/Phe-Ala/Gly-[negatively charged residue]-n/Phe-n/Cys-Thr-Phe/n; second: Gly/Ala-Ile/Leu-Gln/X-[positively charged residue]-NH-n/Cys-Ser/nphi/X-n/Ser-OH/Gly-n-[positively charged residue]-Ile/Met-Gly/Val-n/Thr; fourth: Pro-Asn/ Thr-n-X-[positively charged residue]-Asn/Ser/Ala-n-n-Ile/Leu-n-Asn/Val-Cys/n-n/Thr-[negatively charged residue]-n-n/Thr/Pro-OH/Val (n, nonpolar; phi, aromatic; (positively charged residue/negatively charged residue, charged residue). The second and part of the third signature are also present in the yeast dicarboxylate transporter. The UCP signature excluding BMCP1 was also found in the second matrix segment: [positively charged residue]-(Pro/ del-Leu/del)-[positively charged residue]-phi-X-Gly/Ser-Thr/n-X-NH/[negatively charged residue]-Ala-phi. These UCP signatures are thought to be involved in fatty acid anion binding and translocation.

Amino Acid Motifs↗