- Open Access
Uncoupling proteins, dietary fat and the metabolic syndrome
Nutrition & Metabolism volume 3, Article number: 38 (2006)
There has been intense interest in defining the functions of UCP2 and UCP3 during the nine years since the cloning of these UCP1 homologues. Current data suggest that both UCP2 and UCP3 proteins share some features with UCP1, such as the ability to reduce mitochondrial membrane potential, but they also have distinctly different physiological roles. Human genetic studies consistently demonstrate the effect of UCP2 alleles on type-2 diabetes. Less clear is whether UCP2 alleles influence body weight or body mass index (BMI) with many studies showing a positive effect while others do not. There is strong evidence that both UCP2 and UCP3 protect against mitochondrial oxidative damage by reducing the production of reactive oxygen species. The evidence that UCP2 protein is a negative regulator of insulin secretion by pancreatic β-cells is also strong: increased UCP2 decreases glucose stimulated insulin secretion ultimately leading to β-cell dysfunction. UCP2 is also neuroprotective, reducing oxidative stress in neurons. UCP3 may also transport fatty acids out of mitochondria thereby protecting the mitochondria from fatty acid anions or peroxides. Current data suggest that UCP2 plays a role in the metabolic syndrome through down-regulation of insulin secretion and development of type-2 diabetes. However, UCP2 may protect against atherosclerosis through reduction of oxidative stress and both UCP2 and UCP3 may protect against obesity. Thus, these UCP1 homologues may both contribute to and protect from the markers of the metabolic syndrome.
The uncoupling proteins 1, 2 and 3 (UCP1, UCP2, and UCP3) are members of the super family of anion carrier proteins located in the inner membrane of mitochondria. UCP1 is found only in brown fat mitochondria of mammals. Studies, beginning in the 1960s, identified the function of UCP1 in providing heat and decreasing energy efficiency through dissipation of the proton electrochemical gradient across the inner mitochondrial membrane of brown adipose tissue without the generation of ATP (reviewed in ). Thus, the function of UCP1 was known before the gene was cloned. On the other hand, UCP2  and UCP3 [3, 4], were identified in 1997 by reverse cloning, i.e. by 'mining' databases of expressed sequence tags or from similarity to UCP1 in cDNA libraries (reviewed in ). UCP2 and UCP3 have 59% and 57% identity, respectively, with UCP1, and 73% identity with each other .
Since their cloning in 1997 through July 2006, 945 publications in English, of which 131 are reviews, involving UCP2 and/or UCP3 are listed in the PubMed database , indicating the interest in and the uncertainty regarding the functions of these UCP1 homologues. This brief review will discuss the tissue distribution, reactions, and physiological functions of UCP2 and UCP3. Finally, regulation of these UCPs by dietary fat and the relevance of the UCP proteins to the metabolic syndrome will be discussed. For greater detail on these topics the reader is referred to the following recent reviews [5, 6, 8–11].
UCP2 mRNA is widely distributed with greatest amounts found in spleen, thymus, pancreatic β-cells, heart, lung, white and brown adipose tissue, stomach, testis, and macrophages, and lesser amounts found in brain, kidney, liver, and muscle (reviewed in [5, 10]). Although UCP2 mRNA is found in most organs of the body, there are two difficulties in the determination of which tissues translate UCP2 mRNA into UCP2 protein. First, since UCP2 mRNA is expressed in macrophages, including resident macrophages in several tissues such as brain, liver and lung (reviewed in ), it is difficult to determine if the UCP2 protein is in the macrophages or in the parenchymal cells of the tissue. Second, many early studies used antibodies to UCP2 protein whose specificity was not verified in UCP2 knockout models. Such verification is essential since most "UCP2" antibodies bind to proteins of the same molecular weight as UCP2 even in knockout homozygotes. A few authors have hypothesized, based on Western blots, that UCP2 protein is much less widely distributed than is UCP2 mRNA. However, presence or abundance of UCP2 protein have not been assessed by more sensitive methods. UCP2 protein is clearly found in parenchymal cells of brain, spleen, white adipose tissue and β-cells of the pancreas, and in macrophages in brain, liver and lung but it must be remembered that the amount of UCP2 mRNA may not necessarily predict the amount of UCP2 protein in any tissue or under varying conditions .
Both UCP3 mRNA and protein, on the other hand, are found only in skeletal muscle and in heart. UCP3 mRNA is also found in brown fat, but whether or not the protein has been identified there is controversial.
The primary function of UCP1 is to allow a leak of protons through the inner mitochondrial membrane of brown fat thereby uncoupling substrate oxidation from phosphorylation of ADP to ATP resulting in rapid oxygen consumption, heat production, and energy wastage. This function of UCP1 is mediated by the sympathetic nervous system and norepinephrine in brown adipose tissue and is stimulated by fatty acids and inhibited by purine nucleotides. When UCP2 and UCP3 were first cloned, it was speculated that these proteins would fulfill much the same function, albeit in tissues other than brown fat. However, it quickly became evident that the UCP homologues were not thermogenic to the same degree as UCP1 . Expression of UCP2 and UCP3 can be as much as 1000 fold less than expression of UCP1  and therefore, the expected rate of proton conductance due to UCP2 or UCP3 would be much lower than that produced by UCP1.
Two mechanisms have been proposed to explain the reactions catalyzed by UCP1-3; net proton transport across the membrane and/or export of fatty acid anions (reviewed in [6, 9]) both of which are generally accepted for UCP1. UCP2 and UCP3 do, in fact, increase net proton conductance across the mitochondrial inner membrane, but only when activated either directly or indirectly by superoxide or by derivatives of reactive oxygen species; neither UCP2 nor UCP3 appear to catalyze basal proton conductance. Activation, in turn, requires fatty acids (reviewed in ). Both UCP2 and UCP3, like UCP1, are inhibited by purine nucleotides.
These novel uncoupling proteins have several hypothesized functions including thermogenesis in certain tissues, protection from reactive oxygen species (ROS), mediation of insulin secretion, neuroprotection and export of fatty acids. Several of these functions are related to the etiology of the metabolic syndrome.
Energy wastage and protection from obesity were initially suggested to be significant functions of UCP2 and UCP3 due to their homology to UCP1 and their distribution in tissues, such as white adipose tissue and muscle, that could dissipate energy. Gene expression of UCP2 and UCP3 increases during fasting , opposite of what would be expected for a thermogenic compound, and neither UCP2 nor UCP3 knockout mice are obese [15, 16], providing evidence against these proteins contributing to whole body thermogenesis. Transgenic mice over-expressing a UCP2/UCP3 construct, however, are leaner than wildtype [17, 18] and those overexpressing only UCP3 in skeletal muscle are leaner despite hyperphagia . However, there is a concern that uncoupling in over-expression studies is an artifact and does not reflect the native function of the protein in the cell. Thus, caution is appropriate in ascribing a whole body thermogenic function and protection against obesity to UCP2 or UCP3 (reviewed in [8, 9]).
Two lines of evidence suggest that, under specific conditions, the UCP homologues can have a thermogenic function. Higher temperature is co-localized with UCP2 mRNA within certain areas of the brain suggesting that UCP2 could function as a thermogenic protein in the microenvironment of the brain [20, 21]. In UCP3 knockout mice, the thermogenic response to the drug MDMA (ecstasy) is significantly reduced, suggesting that UCP3 in muscle can affect whole body thermogenesis in this non-physiological condition .
Protection from oxidative damage
ROS production occurs to a large extent in mitochondria and is very sensitive to the mitochondrial membrane potential. When electron flow through the respiratory chain is elevated, 'backed up' electrons may react with oxygen to produce ROS (Figure 1). It is proposed that one function of both UCP2 and UCP3 is to mildly uncouple respiration, allowing a more rapid electron flux, thus reducing membrane potential resulting in reduced ROS production (Figure 2). Superoxides and derivatives of ROS are known to activate GDP-sensitive proton conductance catalyzed by UCP2 or UCP3, thus forming a feedback loop for control of ROS production. Since even mild uncoupling has a large effect on reducing ROS production, this hypothesis has strong support and is now generally accepted (reviewed in [6, 8, 10]. UCP2 knockout mice have elevated ROS production in macrophages  and pancreatic islet cells  and UCP3 knockout mice have elevated ROS in muscle  further supporting the role of these UCPs in protecting against ROS production and tissue oxidative damage.
Mediation of insulin secretion
It is now well established that UCP2 plays an important role in regulation of insulin secretion. Pancreatic β-cells secrete insulin in response to a meal by sensing the ATP/ADP ratio resulting from glucose metabolism in the cell (Figure 1). UCP2, by mildly increasing proton leak, decreases the ATP/ADP ratio of the cell thus reducing the effect of glucose on insulin secretion (Figure 2) (reviewed in [6, 8, 10]). Pancreatic islets from UCP2 knockout mice (UCP2-/-) have increased insulin secretion in response to glucose and these mice have higher blood insulin and lower blood glucose than wildtype supporting the role of UCP2 as a negative regulator of insulin secretion in the whole animal . Double mutant Lepob/ob UCP2-/- mice have improved β-cell function independent of obesity .
A number of studies suggest that UCP2 functions in neuroprotection, including following cerebral ischemia or traumatic injury and prevention of seizures or Parkinson's disease (reviewed in ). UCP2 is found in the inner mitochondrial membranes in several brain regions and is often co-expressed with neuropeptides in both rodents and primates [21, 26]. Several mechanisms contributing to neuronal cell death, including excitotoxicity, mitochondria-mediated cell death and ROS damage are affected by UCP2 (reviewed in ). Exposing the neurons to periods of sub-lethal ischemia preconditions the cells to survive ischemic insults that would normally be lethal. This preconditioning is protein synthesis dependent. UCP2 is upregulated in the hippocampus following ischemic preconditioning , suggesting that UCP2 functions as part of the response to ischemic and oxidative stress in the neurons. Since ROS production and oxidative damage are involved in most neurodegenerative disorders, UCP2 induction was proposed to have a potential therapeutic effect in the treatment of epilepsy, Parkinson's disease, Alzheimer's disease, brain hypoxia and stroke . UCP2, in fact, was shown to have a neuroprotective effect in a mouse model of Parkinson's disease . Opposed to increased UCP2 being neuroprotective is a study showing that UCP2 knockout mice were less sensitive to ischemia following cerebral artery occlusion than wildtype mice . These authors propose that UCP2 is not directly involved in the regulation of ROS production, but rather is acting through regulation of mitochondrial glutathione .
Export of fatty acids
UCP3 has been proposed as a transporter of fatty acid anions out of mitochondria  by analogy with UCP1. The fatty acid cycling model, proposed for UCP1 in 1996 , suggests that UCP3, by transporting fatty acids out of mitochondria, protects the mitochondria from the toxic effects of fatty acid anions or peroxides . The hypothesis is attractive in that it is consistent with observations that UCP3 expression is correlated with improved fatty acid oxidation when fatty acid supplies are high, for example with fasting or a high fat diet (reviewed in [6, 8, 11]). Also, muscle UCP3 protein levels are increased when rats are fed a diet high in long chain triglycerides but not a diet high in medium chain triglycerides which are oxidized via a different pathway , again linking fatty acid oxidation with UCP3. Results from UCP3 knockout mice are not consistent, however, some showing reduced rates of fatty acid oxidation and others no effect (reviewed in [6, 8]. Thus the proposal that UCP3 protects against fatty acid toxicity in the mitochondria remains to be confirmed.
Effect of dietary fat
UCP2 and UCP3 expression is elevated during fasting  or other states, including feeding of high fat diets, where circulating fatty acid levels are elevated and there is a shift from carbohydrate to lipid oxidation (Figures 1 and 2). Most animal models show up-regulation of UCP2 and/or UCP3 by high fat diets [2, 34–37], although this has not been universally observed. Up-regulation of UCP expression depends on strain and tissue type: a high fat diet increased UCP3 mRNA expression in skeletal muscle of C57BL/6J mice  and rats  but increased only slightly UCP2 expression in white adipose tissue of AKR mice and not at all in C57BL/6J mice  or in rats . The up-regulation by a high fat diet of UCP3 protein also occurs in human skeletal muscle .
A high fat, ketogenic diet increases UCP2 mRNA and protein levels and reduces ROS production in the brain [35, 40]. Conversely, substitution of a low fat diet to immature rats reduces UCP2 levels and increases ROS production and seizure-induced excitotoxicity . Thus, the ketogenic diet may be neuroprotective by diminishing ROS production through activation of UCP2 in the brain . Indeed, UCP2 up-regulation in the brain is proposed as the mechanism by which a ketogenic diet reduces pediatric seizures.
Relevance to the metabolic syndrome
Features of the metabolic syndrome include central adiposity, increased plasma triglycerides and free fatty acids, insulin resistance, hyperglycemia, increased inflammation and hypertension, leading to increased risk of type-2 diabetes, atherosclerosis and stroke. Several of these features are influenced by UCP2 and/or UCP3.
Genetic association of natural polymorphisms with phenotypes in humans provides an independent method to determine the in vivo functions of UCP2 and UCP3. Thus, one can demonstrate the influence of UCP2 on type-2 diabetes or BMI in an association study even without proving the underlying biochemical reaction carried out by these proteins. Indeed, genetic studies can be used to guide biochemical studies towards understanding the biochemistry of UCP2 and UCP3.
A review of human genetic studies examining expression of UCP2 or UCP3 and the propensity to obesity suggested that some obesity related phenotypes are significantly associated with these UCPs. A UCP2 insertion/deletion variant was associated with BMI in 4 studies and polymorphisms of UCP3 were associated with BMI in 2 studies (reviewed in ). These authors concluded that since the UCP2 insertion/deletion variant association with BMI was observed in a variety of ethnic groups, the variant itself underlies the association with BMI . Population studies showed that a common polymorphism in the UCP2 promoter, -866G/A, was associated with a reduced risk of obesity in Caucasian Europeans [43, 44]. However, the data suggesting an effect of UCPs on obesity remains uncertain, with two recent papers reporting no linkage or association with UCP2 or UCP3 alleles [45, 46], while another reports association of UCP3 alleles with measures of body composition in women .
As noted above, UCP2 is a regulator of insulin secretion and it is proposed that increased expression of UCP2 in pancreatic β-cells results in chronic down-regulation of glucose stimulated insulin secretion (Figure 2) leading to β-cell dysfunction and the development of type-2 diabetes (reviewed in [6, 8, 10]). Several population studies now show that a common functional polymorphism in the UCP2 promoter (-866G/A, the same polymorphism found to be associated with resistance to obesity in Caucasians) enhances UCP2 transcriptional activity  and increases the risk of developing type-2 diabetes . This polymorphism is associated with impaired β-cell function , impaired insulin sensitivity , and with earlier, more severe diabetes .
Interestingly, the same UCP2 -866G/A polymorphism and a -55C/T polymorphism in UCP3 are both associated with significantly reduced prevalence of diabetic neuropathy in type-1 diabetics . Presumably these polymorphisms prevent mitochondrial mediated neuronal injury and thus protect against diabetic neuropathy. Another common polymorphism in UCP2, -55A/V, was examined in the Coronary Artery Risk Development in Young Adults (CARDIA) study. The -55V/V genotype was positively related to diabetes, perhaps through insulin resistance in individuals with impaired glucose homeostasis . Insulin resistance of type-2 diabetes and obesity involves muscle, liver and adipocytes. UCP2 knockout mice show increased insulin sensitivity and are protected against dietary fat induced insulin resistance . Conversely, data from in vitro studies in L6 muscle cells suggest that UCP3 functions to facilitate fatty acid oxidation and minimize mitochondrial ROS production, perhaps thereby reducing muscle insulin resistance .
The data presently available suggest that UCP2 up-regulation has opposing effects on different components of type-2 diabetes. Increased UCP2 results in β-cell dysfunction, impaired insulin sensitivity, and earlier, more severe diabetes, but may protect from diabetic neuropathy. Thus, UCP2 is proposed as a diabetes gene . Increased UCP3 may, on the other hand, reduce muscle insulin resistance.
UCP2 protects against atherosclerosis in animal models  potentially through inhibition of ROS production in endothelial cells  and inhibition of monocyte accumulation in the artery wall . A common variant in the UCP2 gene is associated with cardiovascular risk in healthy men and with oxidative stress in diabetic men .
Nicholls DG: A history of UCP1. Biochem Soc Trans. 2001, 29 (Pt 6): 751-755. 10.1042/BST0290751.
Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH: Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997, 15 (3): 269-272. 10.1038/ng0397-269.
Boss O, Samec S, Paoloni-Giacobino A, Rossier C, Dulloo A, Seydoux J, Muzzin P, Giacobino JP: Uncoupling protein-3: a new member of the mitochondrial carrier family with tissue-specific expression. FEBS Lett. 1997, 408 (1): 39-42. 10.1016/S0014-5793(97)00384-0.
Vidal-Puig A, Solanes G, Grujic D, Flier JS, Lowell BB: UCP3: an uncoupling protein homologue expressed preferentially and abundantly in skeletal muscle and brown adipose tissue. Biochem Biophys Res Commun. 1997, 235 (1): 79-82. 10.1006/bbrc.1997.6740.
Nedergaard J, Cannon B: The 'novel' 'uncoupling' proteins UCP2 and UCP3: what do they really do? Pros and cons for suggested functions. Exp Physiol. 2003, 88 (1): 65-84. 10.1113/eph8802502.
Krauss S, Zhang CY, Lowell BB: The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol. 2005, 6 (3): 248-261.
Brand MD, Esteves TC: Physiological functions of the mitochondrial uncoupling proteins UCP2 and UCP3. Cell Metab. 2005, 2 (2): 85-93. 10.1016/j.cmet.2005.06.002.
Esteves TC, Brand MD: The reactions catalysed by the mitochondrial uncoupling proteins UCP2 and UCP3. Biochim Biophys Acta. 2005, 1709 (1): 35-44. 10.1016/j.bbabio.2005.06.002.
Mattiasson G, Sullivan PG: The emerging functions of UCP2 in health, disease, and therapeutics. Antioxid Redox Signal. 2006, 8 (1-2): 1-38. 10.1089/ars.2006.8.1.
Schrauwen P, Hesselink MK: The role of uncoupling protein 3 in fatty acid metabolism: protection against lipotoxicity?. Proc Nutr Soc. 2004, 63 (2): 287-292. 10.1079/PNS2003336.
Pecqueur C, Alves-Guerra MC, Gelly C, Levi-Meyrueis C, Couplan E, Collins S, Ricquier D, Bouillaud F, Miroux B: Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. J Biol Chem. 2001, 276 (12): 8705-8712. 10.1074/jbc.M006938200.
Vidal-Puig AJ: Uncoupling expectations. Nat Genet. 2000, 26 (4): 387-388. 10.1038/82489.
Cadenas S, Buckingham JA, Samec S, Seydoux J, Din N, Dulloo AG, Brand MD: UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged. FEBS Lett. 1999, 462 (3): 257-260. 10.1016/S0014-5793(99)01540-9.
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: Lack of obesity and normal response to fasting and thyroid hormone in mice lacking uncoupling protein-3. J Biol Chem. 2000, 275 (21): 16251-16257. 10.1074/jbc.M910177199.
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: Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet. 2000, 26 (4): 435-439. 10.1038/82565.
Horvath TL, Diano S, Miyamoto S, Barry S, Gatti S, Alberati D, Livak F, Lombardi A, Moreno M, Goglia F, Mor G, Hamilton J, Kachinskas D, Horwitz B, Warden CH: Uncoupling proteins-2 and 3 influence obesity and inflammation in transgenic mice. Int J Obes Relat Metab Disord. 2003, 27 (4): 433-442. 10.1038/sj.ijo.0802257.
Fuller PM, Warden CH, Barry SJ, Fuller CA: Effects of 2-G exposure on temperature regulation, circadian rhythms, and adiposity in UCP2/3 transgenic mice. J Appl Physiol. 2000, 89 (4): 1491-1498.
Clapham JC, Arch JR, Chapman H, Haynes A, Lister C, Moore GB, Piercy V, Carter SA, Lehner I, Smith SA, Beeley LJ, Godden RJ, Herrity N, Skehel M, Changani KK, Hockings PD, Reid DG, Squires SM, Hatcher J, Trail B, Latcham J, Rastan S, Harper AJ, Cadenas S, Buckingham JA, Brand MD, Abuin A: Mice overexpressing human uncoupling protein-3 in skeletal muscle are hyperphagic and lean. Nature. 2000, 406 (6794): 415-418. 10.1038/35019082.
Horvath TL, Diano S, Barnstable C: Mitochondrial uncoupling protein 2 in the central nervous system: neuromodulator and neuroprotector. Biochem Pharmacol. 2003, 65 (12): 1917-1921. 10.1016/S0006-2952(03)00143-6.
Horvath TL, Warden CH, Hajos M, Lombardi A, Goglia F, Diano S: Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J Neurosci. 1999, 19 (23): 10417-10427.
Mills EM, Banks ML, Sprague JE, Finkel T: Pharmacology: uncoupling the agony from ecstasy. Nature. 2003, 426 (6965): 403-404. 10.1038/426403a.
Krauss S, Zhang CY, Scorrano L, Dalgaard LT, St-Pierre J, Grey ST, Lowell BB: Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction. J Clin Invest. 2003, 112 (12): 1831-1842. 10.1172/JCI200319774.
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: Energy metabolism in uncoupling protein 3 gene knockout mice. J Biol Chem. 2000, 275 (21): 16258-16266. 10.1074/jbc.M910179199.
Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB: Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes. Cell. 2001, 105 (6): 745-755. 10.1016/S0092-8674(01)00378-6.
Diano S, Urbanski HF, Horvath B, Bechmann I, Kagiya A, Nemeth G, Naftolin F, Warden CH, Horvath TL: Mitochondrial uncoupling protein 2 (UCP2) in the nonhuman primate brain and pituitary. Endocrinology. 2000, 141 (11): 4226-4238. 10.1210/en.141.11.4226.
Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S, Warden CH, Castilho RF, Melcher T, Gonzalez-Zulueta M, Nikolich K, Wieloch T: Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med. 2003, 9 (8): 1062-1068. 10.1038/nm903.
Conti B, Sugama S, Lucero J, Winsky-Sommerer R, Wirz SA, Maher P, Andrews Z, Barr AM, Morale MC, Paneda C, Pemberton J, Gaidarova S, Behrens MM, Beal F, Sanna PP, Horvath T, Bartfai T: Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6-methyl-phenyl-tetrahydropyridine toxicity. J Neurochem. 2005, 93 (2): 493-501. 10.1111/j.1471-4159.2005.03052.x.
de Bilbao F, Arsenijevic D, Vallet P, Hjelle OP, Ottersen OP, Bouras C, Raffin Y, Abou K, Langhans W, Collins S, Plamondon J, Alves-Guerra MC, Haguenauer A, Garcia I, Richard D, Ricquier D, Giannakopoulos P: Resistance to cerebral ischemic injury in UCP2 knockout mice: evidence for a role of UCP2 as a regulator of mitochondrial glutathione levels. J Neurochem. 2004, 89 (5): 1283-1292. 10.1111/j.1471-4159.2004.02432.x.
Himms-Hagen J, Harper ME: Physiological role of UCP3 may be export of fatty acids from mitochondria when fatty acid oxidation predominates: an hypothesis. Exp Biol Med (Maywood). 2001, 226 (2): 78-84.
Garlid KD, Orosz DE, Modriansky M, Vassanelli S, Jezek P: On the mechanism of fatty acid-induced proton transport by mitochondrial uncoupling protein. J Biol Chem. 1996, 271 (5): 2615-2620. 10.1074/jbc.271.5.2615.
Schrauwen P, Hoeks J, Schaart G, Kornips E, Binas B, Van De Vusse GJ, Van Bilsen M, Luiken JJ, Coort SL, Glatz JF, Saris WH, Hesselink MK: Uncoupling protein 3 as a mitochondrial fatty acid anion exporter. Faseb J. 2003, 17 (15): 2272-2274.
Samec S, Seydoux J, Dulloo AG: 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. 1999, 48 (2): 436-441.
Surwit RS, Wang S, Petro AE, Sanchis D, Raimbault S, Ricquier D, Collins S: Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc Natl Acad Sci U S A. 1998, 95 (7): 4061-4065. 10.1073/pnas.95.7.4061.
Sullivan PG, Rippy NA, Dorenbos K, Concepcion RC, Agarwal AK, Rho JM: The ketogenic diet increases mitochondrial uncoupling protein levels and activity. Ann Neurol. 2004, 55 (4): 576-580. 10.1002/ana.20062.
Matsuda J, Hosoda K, Itoh H, Son C, Doi K, Tanaka T, Fukunaga Y, Inoue G, Nishimura H, Yoshimasa Y, Yamori Y, Nakao K: Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their gene expression in rats fed high-fat diet. FEBS Lett. 1997, 418 (1-2): 200-204. 10.1016/S0014-5793(97)01381-1.
Gong DW, He Y, Reitman ML: Genomic organization and regulation by dietary fat of the uncoupling protein 3 and 2 genes. Biochem Biophys Res Commun. 1999, 256 (1): 27-32. 10.1006/bbrc.1999.0239.
Kusunoki M, Tsutsumi K, Iwata K, Yin W, Nakamura T, Ogawa H, Nomura T, Mizutani K, Futenma A, Utsumi K, Miyata T: NO-1886 (ibrolipim), a lipoprotein lipase activator, increases the expression of uncoupling protein 3 in skeletal muscle and suppresses fat accumulation in high-fat diet-induced obesity in rats. Metabolism. 2005, 54 (12): 1587-1592. 10.1016/j.metabol.2005.06.005.
Hesselink MK, Greenhaff PL, Constantin-Teodosiu D, Hultman E, Saris WH, Nieuwlaat R, Schaart G, Kornips E, Schrauwen P: Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo. J Clin Invest. 2003, 111 (4): 479-486. 10.1172/JCI200316653.
Sullivan PG, Springer JE, Hall ED, Scheff SW: Mitochondrial uncoupling as a therapeutic target following neuronal injury. J Bioenerg Biomembr. 2004, 36 (4): 353-356. 10.1023/B:JOBB.0000041767.30992.19.
Sullivan PG, Dube C, Dorenbos K, Steward O, Baram TZ: Mitochondrial uncoupling protein-2 protects the immature brain from excitotoxic neuronal death. Ann Neurol. 2003, 53 (6): 711-717. 10.1002/ana.10543.
Schonfeld-Warden NA, Warden CH: Physiological effects of variants in human uncoupling proteins: UCP2 influences body-mass index. Biochem Soc Trans. 2001, 29 (Pt 6): 777-784. 10.1042/BST0290777.
Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W: A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nat Genet. 2001, 28 (2): 178-183. 10.1038/88911.
Krempler F, Esterbauer H, Weitgasser R, Ebenbichler C, Patsch JR, Miller K, Xie M, Linnemayr V, Oberkofler H, Patsch W: A functional polymorphism in the promoter of UCP2 enhances obesity risk but reduces type 2 diabetes risk in obese middle-aged humans. Diabetes. 2002, 51 (11): 3331-3335.
Berentzen T, Dalgaard LT, Petersen L, Pedersen O, Sorensen TI: Interactions between physical activity and variants of the genes encoding uncoupling proteins -2 and -3 in relation to body weight changes during a 10-y follow-up. Int J Obes (Lond). 2005, 29 (1): 93-99. 10.1038/sj.ijo.0802841.
Guo JJ, Liu YJ, Li MX, Yang YJ, Recker RR, Deng HW: Linkage exclusion analysis of two candidate regions on chromosomes 7 and 11: leptin and UCP2/UCP3 are not QTLs for obesity in US Caucasians. Biochem Biophys Res Commun. 2005, 332 (2): 602-608.
Damcott CM, Feingold E, Moffett SP, Barmada MM, Marshall JA, Hamman RF, Ferrell RE: Genetic variation in uncoupling protein 3 is associated with dietary intake and body composition in females. Metabolism. 2004, 53 (4): 458-464. 10.1016/j.metabol.2003.11.019.
Sesti G, Cardellini M, Marini MA, Frontoni S, D'Adamo M, Del Guerra S, Lauro D, De Nicolais P, Sbraccia P, Del Prato S, Gambardella S, Federici M, Marchetti P, Lauro R: A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes. 2003, 52 (5): 1280-1283.
D'Adamo M, Perego L, Cardellini M, Marini MA, Frontoni S, Andreozzi F, Sciacqua A, Lauro D, Sbraccia P, Federici M, Paganelli M, Pontiroli AE, Lauro R, Perticone F, Folli F, Sesti G: The -866A/A genotype in the promoter of the human uncoupling protein 2 gene is associated with insulin resistance and increased risk of type 2 diabetes. Diabetes. 2004, 53 (7): 1905-1910.
Sasahara M, Nishi M, Kawashima H, Ueda K, Sakagashira S, Furuta H, Matsumoto E, Hanabusa T, Sasaki H, Nanjo K: Uncoupling protein 2 promoter polymorphism -866G/A affects its expression in beta-cells and modulates clinical profiles of Japanese type 2 diabetic patients. Diabetes. 2004, 53 (2): 482-485.
Rudofsky GJ, Schroedter A, Schlotterer A, Voron'ko OE, Schlimme M, Tafel J, Isermann BH, Humpert PM, Morcos M, Bierhaus A, Nawroth PP, Hamann A: Functional polymorphisms of UCP2 and UCP3 are associated with a reduced prevalence of diabetic neuropathy in patients with type 1 diabetes. Diabetes Care. 2006, 29 (1): 89-94. 10.2337/diacare.29.01.06.dc05-0757.
Yu X, Jacobs DRJ, Schreiner PJ, Gross MD, Steffes MW, Fornage M: The uncoupling protein 2 Ala55Val polymorphism is associated with diabetes mellitus: the CARDIA study. Clin Chem. 2005, 51 (8): 1451-1456. 10.1373/clinchem.2004.044859.
Joseph JW, Koshkin V, Zhang CY, Wang J, Lowell BB, Chan CB, Wheeler MB: Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes. 2002, 51 (11): 3211-3219.
MacLellan JD, Gerrits MF, Gowing A, Smith PJ, Wheeler MB, Harper ME: Physiological increases in uncoupling protein 3 augment fatty acid oxidation and decrease reactive oxygen species production without uncoupling respiration in muscle cells. Diabetes. 2005, 54 (8): 2343-2350.
Marx J: Unraveling the causes of diabetes. Science. 2002, 296 (5568): 686-689. 10.1126/science.296.5568.686.
Blanc J, Alves-Guerra MC, Esposito B, Rousset S, Gourdy P, Ricquier D, Tedgui A, Miroux B, Mallat Z: Protective role of uncoupling protein 2 in atherosclerosis. Circulation. 2003, 107 (3): 388-390. 10.1161/01.CIR.0000051722.66074.60.
Lee KU, Lee IK, Han J, Song DK, Kim YM, Song HS, Kim HS, Lee WJ, Koh EH, Song KH, Han SM, Kim MS, Park IS, Park JY: Effects of recombinant adenovirus-mediated uncoupling protein 2 overexpression on endothelial function and apoptosis. Circ Res. 2005, 96 (11): 1200-1207. 10.1161/01.RES.0000170075.73039.5b.
Ryu JW, Hong KH, Maeng JH, Kim JB, Ko J, Park JY, Lee KU, Hong MK, Park SW, Kim YH, Han KH: Overexpression of uncoupling protein 2 in THP1 monocytes inhibits beta2 integrin-mediated firm adhesion and transendothelial migration. Arterioscler Thromb Vasc Biol. 2004, 24 (5): 864-870. 10.1161/01.ATV.0000125705.28058.eb.
Dhamrait SS, Stephens JW, Cooper JA, Acharya J, Mani AR, Moore K, Miller GJ, Humphries SE, Hurel SJ, Montgomery HE: Cardiovascular risk in healthy men and markers of oxidative stress in diabetic men are associated with common variation in the gene for uncoupling protein 2. Eur Heart J. 2004, 25 (6): 468-475. 10.1016/j.ehj.2004.01.007.
The author(s) declare that they have no competing interests.
Authors’ original submitted files for images
Below are the links to the authors’ original submitted files for images.
Rights and permissions
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Fisler, J.S., Warden, C.H. Uncoupling proteins, dietary fat and the metabolic syndrome. Nutr Metab (Lond) 3, 38 (2006). https://doi.org/10.1186/1743-7075-3-38
- Reactive Oxygen Species Production
- Brown Adipose Tissue
- White Adipose Tissue
- Proton Conductance
- Ketogenic Diet