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An Update HESSELINK, MATTHIJS K.C., MARCO MENSINK, AND PATRICK SCHRAUWEN. Human uncoupling protein-3 and obesity: an update. Obes Res. 2003;11: 1429 1443. The cloning of the uncoupling protein (UCP)1 homologs UCP2 and UCP3 has raised considerable interest in the mechanism. The expression of UCP3 mainly in skeletal muscle mitochondria and the potency of the skeletal muscle as a thermogenic organ made UCP3 an attractive target for studies toward manipulation of energy expenditure to fight disorders such as obesity and type 2 diabetes. Overexpress- ing UCP3 in mice resulted in lean, hyperphagic mice. How- ever, the lack of an apparent phenotype in mice lacking UCP3 triggered the search for alternative functions of UCP3. The observation that fatty acid levels significantly affect UCP3 expression has given UCP3 a position in fatty acid handling and/or oxidation. Emerging data indicate that the primary physiological role of UCP3 may be the mito- chondrial handling of fatty acids rather than the regulation of energy expenditure through thermogenesis. It has been proposed that UCP3 functions to export fatty acid anions away from the mitochondrial matrix. In doing so, fatty acids are exchanged with protons, explaining the uncoupling ac- tivity of UCP3. The exported fatty acid anions may origi- nate from hydrolysis of fatty acid esters by a mitochondrial thioesterase, or they may have entered the mitochondria as nonesterified fatty acids by incorporating into and flip- flopping across the mitochondrial inner membrane. Regard- less of the origin of the fatty acid anions, this putative function of UCP3 might be of great importance in protect- ing mitochondria against fatty acid accumulation and may help to maintain muscular fat oxidative capacity. energy expenditure, reactive oxygen species, lipotoxicity energy needed to fuel cellular processes like ion pumping, muscular contraction, protein synthesis, and degradation of nutrients in the digestive tract. In all these processes, hy- drolysis of adenosine triphosphate (ATP), of utmost importance that ATP levels are maintained, even under conditions of severe energy stress. The vast majority of ATP is synthesized in a process referred to as mitochon- drial oxidative phosphorylation. Degradation of nutrients like proteins, carbohydrates, and lipids ultimately results in the production of the co-enzymes nicotinamide adenine dinucleotide and flavin adenine dinucleotide, which can, in turn, be oxidized to nicotinamide adenine dinucleotide (NAD ) and flavin adenine dinucleotide and H electron transfer or respiratory chain, is located in the inner mitochondrial membrane. According to the chemiosmotic theory defined by Mitchell and Moyle (1), the electron transfer chain results in a net proton gradient across the inner mitochondrial membrane. If the proton gradient is high enough, the protons may flow back to the mitochon- drial matrix through the F generate ATP (oxidative phosphorylation). In tightly cou- pled mitochondria, there is no proton leak across the inner mitochondrial membrane, and all the energy built up in the respiratory chain can be used for (is coupled to) generation of ATP. Accepted in final form October 3, 2003. *Department of Movement Sciences and Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, The Nether- lands. Address correspondence to Matthijs K.C. Hesselink, Department of Movement Sciences, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands. E-mail: matthijs.hesselink@bw.unimaas.nl Copyright © 2003 NAASO hUCP3, human uncoupling protein-3; ROS, reactive oxygen species; FFA, free fatty acid; PPAR, peroxisome proliferator-activated receptor. |
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