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bination of decreased TCA cycle flux with decreased ATP synthesis rate has been presented as a lack of effect on mitochondrial uncoupling (33). Thus, under pathophysio- logical conditions like hypo- or hyperthyroidism, UCP3- mediated uncoupling cannot be excluded. cently showed that supplying subjects isocaloric high-fat vs. low-fat diets (60% of energy as fat vs. 30% of energy as fat with identical protein levels) resulted in a significant in- crease in UCP3 protein levels within the physiological range within 7 days (34). After severe exhaustive ischemic contractile activity, mitochondrial coupling was measured in vivo by measuring creatine phosphate resynthesis rate after blood flow was reinstated. We concluded that, despite a 44% increase in UCP3 protein content and with all po- tential physiological modulators of UCP3 activity present, mitochondrial coupling was not affected (34), suggesting that mitochondrial uncoupling may not be the principal function of UCP3 in vivo. UCP3-tg mice, with characteristics apparently beneficial in the treatment of obesity, is most likely caused by uncou- pling. Because the uncoupling in UCP3-tg mice is nonin- ducible, it is considered artificial, possibly because of mis- folded UCP3 and/or UCP3 loosely imported into the inner mitochondrial membrane. However, immunoelectron mi- croscopy studies have shown that, in the UCP3-tg mice, almost all UCP3 expressed is confined to the mitochondria, in contrast to observations in yeast. The UCP3-ko mice lack an apparent phenotype, and reports on proton leak are inconsistent. These findings indicate that 1) the phenome- non uncoupling per se (inducible or noninducible) may be advantageous in the prevention or treatment of obesity; and 2) it is, however, unlikely that under physiological condi- tions, human UCP3 is a major contributor to the basal proton leak, possibly with an exception for T3-induced thermogenesis. Therefore, based on these studies, a role for UCP3 in energy metabolism would not be anticipated. Nev- ertheless, many studies have examined the effect of physi- ological interventions that alter energy metabolism on UCP3 expression to unravel the role of UCP3 in human physiology and possibly the regulation of body mass. within 7 kb of the UCP2 gene on chromosome 11q13, a region that has been linked to obesity and hyperinsulinemia (5). Several polymorphisms in the UCP3 gene have been identified (36 42) and related to markers of energy metab- olism and obesity. We have recently reviewed the effect of UCP3 polymorphisms known so far and concluded that the effect on markers of obesity shows inconsistent results (43). resulting in an apparent null mutation of UCP3, reported in Gullah-speaking African Americans with early onset severe obesity (BMI significant (p authors to suggest that UCP3 may increase fat oxidation by introducing fatty acids into the mitochondrial matrix (44) and explain the declined fat oxidation in the carriers of the polymorphism. In later studies in African Americans (45) or in Danish whites (46), carriers of the exon 6-splice donor mutation showed no changes in resting metabolic rate or fuel partitioning. significant role for UCP3 in the regulation of energy expen- diture, although a role of UCP3 in substrate metabolism in selected populations cannot be excluded. was estimated that contribution of skeletal muscle to adrenalin-induced in- creased energy expenditure were made (48). Given the skeletal musclespecific expression of UCP3, it is tempting to relate the mRNA in white adipose tissue and, to a lesser extent, in skeletal muscle (8). Using the same compound, similar observations were made in obese rats treated for 10 days (49). This finding, however, could not be reproduced by others using trecadrine as a agonists) increased UCP3 mRNA levels, whereas propran- olol (a tion-induced thermogenesis. However, observations of in- creases in UCP3 after |
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