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suffering from chronic respiratory disease have decreased mechanical efficiency (75) while having lower UCP3 pro- tein content (76). acid metabolism. This has led to the suggestion that UCP3 is involved in the regulation of lipids as fuel substrate rather than as a mediator of regulatory thermogenesis (77). This suggestion was based, for the most part, on the tissue- dependent differential mRNA expression of the UCP ho- mologs in skeletal muscles of distinct fiber typology, which is consistent with the differential requirement of these tis- sues for lipids during fasting and their ability to shift from glucose to fat oxidation during refeeding and exercise. Thus, it was shown that increases in UCP3 mRNA, under conditions of elevated FFA levels, were more pronounced in muscles comprised of fibers enzymatically equipped for glycolysis (type IIa and IIx fibers) than in muscles made of slow (type I) fibers with a high fat oxidative capacity (55,78). In addition, when examined at the cellular level, protein expression of UCP3 was most prominent in glyco- lytic type IIb (or type IIx) fibers, with somewhat lower expression in type IIa fibers and the lowest expression in the fat oxidative type I fibers, in healthy humans and type 2 diabetics (20,70). Given the low expression of fat oxidative enzymes in type IIx fibers and the high level of UCP3 expression, it is not conceivable that UCP3 serves to facil- itate fat oxidation. Also, decreased UCP3 content in skeletal muscle of endurance-trained athletes (70), known for their high fat oxidative capacity, does not favor the idea that UCP3 plays a major role in modulating fat oxidation. In fact, when lean, previously untrained subjects participated in a 3-month training program, their fat oxidative capacity increased significantly (79), whereas plasma FFA levels remained unaltered. Analyses of UCP3 protein content pre- and post-training revealed that training induced a decrease in UCP3. This decrease in UCP3 negatively correlated with the training-induced increase in fat oxidation; i.e., the sub- jects with the most prominent increase in fat oxidative capacity showed the most prominent decrease in UCP3 protein (71). The high capacity to oxidize fats in trained athletes may also be the reason for the observation that consumption of a high-fat diet for 5 days failed to affect UCP3 mRNA levels in athletes (64), whereas feeding a diet with comparable high levels of fat to normal healthy sub- jects (with normal fat oxidative capacity) for 7 days resulted in up-regulation of UCP3 at the protein level (34). regulation, which was anticipated if the role of UCP3 was to modulate fat oxidation. Another model in which fat oxida- tive capacity is increased while plasma FFA levels are reduced is after weight reduction induced by caloric restric- tion for 10 weeks. Under these conditions, we have reported decreased UCP3 protein levels that correlated well with skeletal muscle fatty acid binding protein content (19). Interestingly, in obese patients (BMI (55%) was paralleled by significant reductions in UCP3 mRNA (45%) and protein (35%) (80). Thus, despite down- regulation of UCP3, a massive reduction in body mass was observed, indicating that UCP3 plays no obligatory role in loss of body mass. levels without improved fat oxidation capacity, such as fasting, acute exercise, and fatty acid infusion. In experi- mentally induced diabetes in rodents by administration of streptozotocin, fatty acid levels rise acutely without instan- taneous effects on fat oxidative capacity. Indeed, increased UCP3 levels have been reported at the mRNA level after administration of streptozotocin (81,82). acid delivery and fat oxidation or, more precisely, if the supply of fatty acids to the mitochondria exceeds the ca- pacity of the mitochondria to oxidize fatty acids. UCP3: A Hypothesis fatty acids need to cross the outer and the inner mitochon- drial membrane. Whereas nonesterified (free) fatty acids can cross the outer mitochondrial membrane, transport across the inner mitochondrial membrane is more intricate. Transport across the inner mitochondrial membrane is, in general, facilitated by the carnitine acyltransferase system (CAT1 and CAT 2), which catalyzes the transport of fatty acyl-coenzyme A (acylCoA) esters. Outside the mitochon- dria, fatty acids are esterified by fatty acylCoA synthetase, resulting in fatty acylCoA, which, in turn, is converted into acylcarnitine by CAT1. Acylcarnitine crosses the inner mi- tochondrial membrane, where it is reconverted to fatty acyl- CoA by CAT2. Only in this form can fatty acids be de- graded in the -oxidation to acetylCoA, which, in turn, may enter the TCA cycle. Any defect in uptake through the carnitine acyltransferase system or downstream in -oxida- tion will lead to decreased fat oxidation. when fatty acids are incorporated into the phospholipid |
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