METABOLISM AND BIOENERGETICS
Energy Metabolism in Uncoupling Protein 3 Gene Knockout Mice*

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Uncoupling protein 3 (UCP3) is a member of the mitochondrial anion carrier superfamily. Based upon its high homology with UCP1 and its restricted tissue distribution to skeletal muscle and brown adipose tissue, UCP3 has been suggested to play important roles in regulating energy expenditure, body weight, and thermoregulation. Other postulated roles for UCP3 include regulation of fatty acid metabolism, adaptive responses to acute exercise and starvation, and prevention of reactive oxygen species (ROS) formation. To address these questions, we have generated mice lacking UCP3 (UCP3 knockout (KO) mice). Here, we provide evidence that skeletal muscle mitochondria lacking UCP3 are more coupled (i.e. increased state 3/state 4 ratio), indicating that UCP3 has uncoupling activity. In addition, production of ROS is increased in mitochondria lacking UCP3. This study demonstrates that UCP3 has uncoupling activity and that its absence may lead to increased production of ROS. Despite these effects on mitochondrial function, UCP3 does not seem to be required for body weight regulation, exercise tolerance, fatty acid oxidation, or cold-induced thermogenesis. The absence of such phenotypes in UCP3 KO mice could not be attributed to up-regulation of other UCP mRNAs. However, alternative compensatory mechanisms cannot be excluded. The consequence of increased mitochondrial coupling in UCP3 KO mice on metabolism and the possible role of yet unidentified compensatory mechanisms, remains to be determined.

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Published, JBC Papers in Press, March 22, 2000, DOI 10.1074/jbc.M910179199

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This work was supported by National Institutes of Health Grant DK49569 (to B. B. L.), a grant from Lilly (to B. B. L.), Boston Obesity Nutrition Research Center (BONRC) Pilot Project Award P30 DK46200 (to A. V.-P.), BONRC Transgenic Core Grant P30 DK46200, and Human Frontier Science Program Grant LT 0020/1999 (to O. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Present address: University of Cambridge, Depts. of Clinical Biochemistry and Medicine, Addenbrooke's Hospital, Box 232, Cambridge CB2 2QR, UK.