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(UCP2) and Uncoupling Protein-3 (UCP3) Expression in Adipose Tissue and Skeletal Muscle in Humans

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(UCP2) and Uncoupling Protein-3 (UCP3) Expression in Adipose Tissue and Skeletal Muscle in Humans International Journal of Obesity (1999) 23, Suppl 6, S64±S67 ß 1999 Stockton Press All rights reserved 0307±0565/99 $12.00 http://www.stockton-press.co.uk/ijo Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) expression in adipose tissue and skeletal muscle in humans D Langin1*, D Larrouy1, P Barbe1, L Millet1, N Viguerie-Bascands1, F Andreelli2, M Laville2 and H Vidal2 1Unite INSERM 317, Institut Louis Bugnard, Universite Paul Sabatier, HoÃpital Rangueil, Toulouse, France; and 2Unite INSERM 449 et Centre de Recherche en Nutrition Humaine de Lyon, Faculte de MeÂdecine LaeÈnnec, Lyon, France Uncoupling protein-2 (UCP2) and uncoupling protein-3 (UCP3) are mitochondrial proteins that may play a role in the control of energy expenditure by uncoupling respiration from ATP synthesis. The present review focuses on data obtained in humans. UCP2 is widely expressed in the body, whereas UCP3 expression is restricted to skeletal muscle. Positive correlations have been reported between UCP2 mRNA concentrations in adipose tissue, UCP3 mRNA concentrations in skeletal muscle, and components of the metabolic rate. Fasting induces an up-regulation of UCP2 and UCP3 mRNA expression. In vivo and in vitro studies suggest that fatty acids could modulate uncoupling protein gene expression. The putative relationship between obesity, energy expenditure and uncoupling protein expression, and the unexpected rise in UCP2 and UCP3 mRNA concentrations during short-term fasting, are discussed in view of the recent data obtained in rodents and cell lines. Keywords: energy expenditure; fatty acid; adipose tissue; skeletal muscle; obesity; Uncoupling protein-2 (UCP2) and UCP3 mRNAs are markedly different. UCP2 mRNA is widely expressed in the body whereas the main site uncoupling protein-3 (UCP3) of UCP3 mRNA expression is skeletal muscle in adult expression and isoforms in humans humans. UCP3 mRNA exists as long and short form transcripts.3 The two transcripts are generated from a single gene, through alternative splicing and use of The two novel uncoupling proteins known as UCP2 polyadenylation signals.8 The short form transcript and UCP3 may be the long-awaited `missing link' in encodes a putative protein, designated UCP3 , that the understanding of the molecular basis of energy S does not contain the last 37 amino acids present in the expenditure in humans. The resting metabolic rate long form UCP3 (UCP3 ), UCP1 and UCP2. This (RMR), that is, the obligatory energy expenditure L region contains the putative sixth transmembrane required to maintain physiological tissue function in domain and motifs likely to be critical for uncoupling the resting state, is the largest component of daily activity. UCP3 could show an increased uncoupling energy expenditure. A substantial part of the RMR S activity because of the lack of a conserved motif that results from a leaking of protons across the mitochon- mediates inhibition of UCP1 uncoupling activity by drial inner membrane, which results in energy dis- purine nucleotides. It is also possible that UCP3 may sipation because of uncoupling of oxygen S not be stable or may not be functional in the mito- consumption to ATP synthesis.1,2 UCP2 and UCP3 chondrial inner membrane. The effect of mutations are candidates to explain the proton leak in many recently found in the human UCP3 gene9 is in tissues.3±6 UCP2 and UCP3 expression in yeast accordance with a defective function of UCP3 .A indeed causes a decrease in mitochondrial membrane S mutation at the exon 6-splice donor site, detected in potential. The two proteins show sequence identity African-Americans, results in the premature termina- with UCP1, an uncoupling protein expressed in brown tion of the protein product which is identical to adipose tissue (BAT). In rodents, but probably not in UCP3 . Heterozygotes for the mutation showed a adult humans, BAT is an important site of adaptive S 50% reduction in fat oxidation and an elevation of thermogenesis.7 The tissue distribution of UCP2 and the nonprotein respiratory quotient (RQ), compared with wild-type subjects. The frequency of the muta- tion was twice as high in obese, compared with lean, individuals. Variation in the ratio between UCP3L and Correspondence: Dr Dominique Langin, INSERM U317, Institut Louis Bugnard, Baà timent L3, CHU Rangueil, 31403 Toulouse UCP3S could therefore modulate skeletal muscle Cedex 4, France. uncoupling activity. Tissue UCP2 and UCP3 D Langin et al S65 Uncoupling protein mRNA represent most of the adipose tissue mass in humans. Therefore, the data suggest that the concen- concentrations, energy expenditure tration of UCP2 mRNA in subcutaneous adipose and obesity tissue re¯ects the overall level of UCP2 gene expres- sion in total body fat. Hence, the positive correlation Because a low rate of energy expenditure is a predis- found between RMR and subcutaneous adipose tissue posing factor for weight gain and the potential link UCP2 mRNA concentration might be extended to between uncoupling protein expression and RMR, UCP2 mRNA concentration in whole body fat. Ober- several laboratories, including ours, have sought to ko¯er et al16 have reported a reduced UCP2 mRNA determine the factors modulating UCP2 and UCP3 expression in visceral adipose tissue of a large number gene expression in human skeletal muscle and adipose of morbidly obese subjects. As the authors indicate, tissue. We have developed a reverse transcription- the possible role of the lower UCP2 expression in the competitive polymerase chain reaction (RT-cPCR) pathophysiology of obesity remains to be proven. assay to determine UCP2 and UCP3 mRNA concen- In rodents, a potential role for white adipose tissue trations.11 Because of the important differences (WAT) UCP2 in the regulation of body weight and between UCP3L and UCP3S, the two mRNAs were energy expenditure is suggested by several lines of quanti®ed separately.12 In the vastus lateralis muscle, evidence. A high fat diet increases WAT UCP2 gene UCP3 mRNA is more abundant than UCP2 mRNA, as expression in the obesity-resistant A=J and C57BL= 3,6 also found in rodents. UCP3L and UCP3S are KsJ strains, but not in the obesity-prone C57BL=6J expressed in equal amounts. No large difference in mice. Interestingly, the diet does not affect UCP2 and the level of the three transcripts was observed between UCP3 mRNA expression in skeletal muscle.4,17 Caucasian obese and lean individuals.11,12 Using in UCP1-de®cient mice do not become obese and it situ hybridisation, a 30% lower UCP2 mRNA expres- was proposed that the lack of UCP1 may be compen- sion was reported by Norfors et al13 in skeletal muscle sated by UCP2.18 Moreover, the ectopic expression of of obese subjects. In agreement with our data,11 UCP3 UCP1 in WAT results, in transgenic mice, in a mRNA concentrations were similar in the two groups. decrease of adiposity attributed to an increase of In contrast, Schrauwen et al14 showed a negative energy dissipation in this tissue.19, 20 A similar role correlation between UCP3L mRNA concentrations for adipose tissue UCP2 in energy dissipation remains and body mass index (BMI) in Pima Indians that to be demonstrated. was not found with UCP2 mRNA levels. The lower susceptibility to obesity of Caucasians compared with Pima Indians might explain such a discrepancy. Stu- dies on a large number of individuals with a wide Variations in uncoupling protein range of BMI are clearly needed to clarify this point. gene expression during fasting Nevertheless, in line with a putative role of skeletal muscle UCP3 in the control of energy expenditure, a positive correlation was found in Pima Indians Possible modulation of uncoupling protein gene between sleeping metabolic rate (SMR) adjusted for expression was studied during a ®ve-day severe cal- fat-free mass (FFM) and fat mass (FM) and UCP3L orie restriction, a situation associated with a decrease mRNA concentrations.14 in energy expenditure.11,12 Unexpectedly, the fasting In subcutaneous adipose tissue, we found a positive condition induced a 2 ± 3 fold increase of UCP2, correlation between BMI and UCP2 mRNA concen- UCP3L and UCP3S mRNA concentrations. Similar trations.11 This data is consistent with the higher ®ndings have been reported in rodents.21,22 The induc- UCP2 mRNA concentration found in white adipose tion was similar in lean and obese subjects suggesting tissue of ob=ob and db=db obese mice, compared with that, during fasting, there is no major alteration of lean littermates,5 suggesting a possible relationship uncoupling protein gene regulation in obesity. The between the concentration of UCP2 mRNA and fat signi®cance of this observation is not clear at the cell hypertrophy. A potential link between UCP2 and present time. Study of UCP2 and UCP3 gene expres- energy expenditure was studied in obese premenopau- sion during fasting and refeeding in rodents has led to sal women.15 After standardisation of food intake by a the proposal that UCP2 and UCP3 would act as four week very-low-calorie diet (VLCD), a positive regulators of lipids as a fuel substrate rather than as correlation was found between subcutaneous adipose a mediator of regulatory thermogenesis.22 In agree- tissue UCP2 mRNA concentration and RMR adjusted ment with this hypothesis, mutations in the human for FFM, but the correlation failed to reach signi®- UCP3 gene have been associated with a decreased cance before the diet. Factors other than RMR (for capacity of fat oxidation.9 The hypothesis needs, example, the diet composition) are therefore likely to however, to be substantiated by studying the relation- be associated with UCP2 mRNA concentrations in ship between mitochondrial uncoupling proteins and adipose tissue. A strong correlation was found intracellular lipid metabolism. It is important to stress between subcutaneous and visceral adipose tissue that the increase in uncoupling protein mRNA con- UCP2 mRNA concentrations.
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