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effect of -stimulation from the effect of increased lipolysis on skeletal muscle UCP3 expression, we recently studied the effect of salbutamol infusion with and without acipimox (to block lipolysis) in humans. We found that salbutamol infusion did not increase UCP3 mRNA levels, but lowering FFA levels by blocking lipolysis with acipimox during salbutamol infusion resulted in a decrease in UCP3 mRNA (52). These results might imply that increasing FFA levels. Nevertheless, no studies have been performed that directly examine the effect of sibility open that uncoupling is involved in Expression study in rodents, it was shown that a 48-hour fast induced a 5.6-fold increase in UCP3 mRNA in the rat tibialis anterior muscle and that 24-hour fasting induced a 3.5-fold increase in UCP3 mRNA in the mouse soleus muscle without affect- ing basal heat production in vitro (54). These seemingly paradoxical observations, i.e., increased expression of UCP3 under conditions of attenuated energy expenditure, were put into perspective when plasma FFA levels were taken into consideration. Fatty acids have long been recog- nized as potent regulators of gene transcription for numer- ous genes. Indeed, it was shown that the 10-fold increase in UCP3 in rats fasted for 24 to 72 hours could be mimicked by elevation of fatty acid levels (by infusion of Intralipid together with heparin; Pharmacia, Clayton, NC), whereas other physiological responses known to occur during fasting (a fall in leptin and increased corticosterone levels) had no effect on UCP3 mRNA (55). In addition, a fasting-induced (30 hour) increase in UCP3 mRNA was completely re- versed within 2 hours of refeeding (56). The importance of fatty acids in induction of UCP3 is further illustrated by the observation that, in skeletal and heart muscle from fetal mice, UCP3 is not induced until lactation with high levels of fat, whereas a high-carbohydrate diet at weaning induces a decrease in UCP3 mRNA levels (57). control mice and UCP3-ablated mice. Again, fasting in- duced up-regulation of UCP3 mRNA in control mice but did not affect proton motive force and state 4 respiration (58). Interestingly, this was the first study to report in- creased respiratory exchange ratio values if UCP3-ko mice had ad libitum access to food compared with ad libitumfed controls (58). Fasting attenuated these differences, albeit supportive of the idea that UCP3 plays an important role in fat oxidation (58). Because subjects with decreased fat oxidative capacity are prone to developing obesity (59), the increased respiratory rate observed in UCP3-ablated mice could indicate that a complete lack of UCP3 may, in the long run, increase the propensity for obesity. With respect to this, it is of relevance to note that, in carriers of the exon 6-splice donor mutation, resulting in the absence of UCP3, conflicting data have been reported on respiratory exchange values. indicated, among others, by observations in weaning mice (60). In 5-week-old rats, UCP3 was induced on isocaloric high-fat feeding in gastrocnemius muscle and was reported to depend on both chain length of the fatty acids as well as on the extent of saturation (61). Feeding rats, ad libitum, a high-fat (60% of energy from fat) vs. a low-fat diet (12% of energy from fat) resulted in significant elevations in plasma FFA levels and induced a 2-fold increase in UCP3 protein level after 4 weeks of feeding, without affecting mitochon- drial uncoupling or 24-hour energy expenditure (62). In humans, consumption of a high-fat diet by healthy, trained athletes for 4 weeks (41% of energy from fat vs. 17% of energy from fat) also resulted in increased UCP3 mRNA expression, with the most prominent results in humans with a high percentage of type IIa muscle fibers (63). In a recent study, feeding well-trained subjects high- and low-fat diets (65% of energy from fat vs. 70% to 75% of energy as carbohydrate) for only 5 days in a crossover design did not affect UCP3 gene expression, in contrast to other genes involved in lipid metabolism (64). The lack of effect of a high-fat diet on UCP3 may have been because of the rela- tively short period of high-fat consumption, possibly in combination with the selection of subjects recruited. high-fat diet, consistently results in induction of the UCP3 gene, with concordant changes in UCP3 protein content. This increase seems to depend on chain length and the extent of saturation of the fatty acids ingested. In none of the cases reporting increased UCP3 mRNA or protein levels was evidence found linking fatty acidinduced increased UCP3 to increased mitochondrial uncoupling. Thus, it seems that UCP3 does not play a major role in the preven- tion of high-fat dietinduced obesity. Expression metabolism or fatty acid oxidation. Therefore, the effect of exercise on UCP3 regulation has been studied extensively. |
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