Energy Metabolism in Uncoupling Protein 3 Gene Knockout Mice*

By Antonio Vidal-Puig, D. Grujic, Chen-Yu Zhang, T. Hagen, O. Boss, Y. Ido, Alicja Szczepanik, J. Wade, Vamsi K. Mootha, R. Cortright and 2 more. Journal of Biological Chemistry, 2000

720 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Physiology, Surgery

View Paper: https://www.semanticscholar.org/paper/6bf1c6a3dbd0459f8449f4c1d25f4d74e5160412

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Citations in the corpus

• Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells (2005, positive): “In one example, mitochondria from UCP3 KO mice generated higher levels of superoxide [53,54], suggesting that some degree of uncoupling can be beneficial by controlling reactive oxygen species production [55].”
• The mitochondrial uncoupling-protein homologues (2005, background): “Mitochondria that are isolated from the skeletal muscle of UCP3 -knockout mice show decreased proton lea”
• Mitochondrial electron transport chain, ROS generation and uncoupling (Review) (2019, background): “Experiments have demonstrated that ROS production is increased in UcP2/3-ablated mice (184-186).”
• Fucoxanthin from edible seaweed, Undaria pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues. (2005, background): “Indeed , unexpected physiological or pathological implications of the UCP2 and UCP3 function were indicated [2], such as the possible UCP2 involvement in diabetes and in apoptosis.”
• Calorie restriction, SIRT1 and metabolism: understanding longevity (2005, background): “How might changes in UCPs affect cells? Mitochondria from UCP3-knockout mice show increased superoxide generatio”
• Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. (2001, methodology): “Taken together, the stud(Vidal-Puig et al., 2000), using a medium containing 250 mM sucrose, ies presented here suggest a possible anticachectic 5 mM Tris, and 2 mM EGTA (pH 7.”
• Transcriptional regulation of gene expression in human skeletal muscle during recovery from exercise. (2000, background): “Although the physiological role of HO-1 in muscle has not been established, partially reduced ROS are produced in human skeletal muscle during intense exercise (14).”
• Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production (2000, background): “A higher level of ROS was recently measured in skeletal muscle of mice deficient for Ucp3 (ref”
• Superoxide activates mitochondrial uncoupling proteins (2002, background): “UCP2 and UCP3 are present at much lower abundance than UCP1, and the uncoupling with which they are associated is not significantly thermogeni”