Decreased Mitochondrial Proton Leak and Reduced Expression of Uncoupling Protein 3 in Skeletal Muscle of Obese Diet-Resistant Women

  1. Mary-Ellen Harper1,
  2. Robert Dent12,
  3. Shadi Monemdjou1,
  4. Véronic Bézaire3,
  5. Lloyd Van Wyck14,
  6. George Wells1,
  7. Gul Nihan Kavaslar3,
  8. Andre Gauthier14,
  9. Frédérique Tesson13 and
  10. Ruth McPherson13
  1. 1University of Ottawa Faculty of Medicine, Ottawa, Canada
  2. 2Ottawa Hospital Weight Management Clinic, Ottawa, Canada
  3. 3University of Ottawa Heart Institute, Ottawa, Canada
  4. 4Ottawa Hospital, Ottawa, Canada


    Weight loss in response to caloric restriction is variable. Because skeletal muscle mitochondrial proton leak may account for a large proportion of resting metabolic rate, we compared proton leak in diet-resistant and diet-responsive overweight women and compared the expression and gene characteristics of uncoupling protein (UCP)2 and UCP3. Of 1,129 overweight women who completed the University of Ottawa Weight Management Clinic program, 353 met compliance criteria and were free of medical conditions that could affect weight loss. Subjects were ranked according to percent body weight loss during the first 6 weeks of a 900-kcal meal replacement protocol. The highest and lowest quintiles of weight loss were defined as diet responsive and diet resistant, respectively. After body weight had been stable for at least 10 weeks, 12 of 70 subjects from each group consented to muscle biopsy and blood sampling for determinations of proton leak, UCP mRNA expression, and genetic studies. Despite similar baseline weight and age, weight loss was 43% greater, mitochondrial proton leak-dependent (state 4) respiration was 51% higher (P = 0.0062), and expression of UCP3 mRNA abundance was 25% greater (P < 0.001) in diet-responsive than in diet-resistant subjects. There were no differences in UCP2 mRNA abundance. None of the known polymorphisms in UCP3 or its 5′ flanking sequence were associated with weight loss or UCP3 mRNA abundance. Thus, proton leak and the expression of UCP3 correlate with weight loss success and may be candidates for pharmacological regulation of fat oxidation in obese diet-resistant subjects.


    • Address correspondence and reprint requests to Dr. M.-E. Harper, Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, Ontario, Canada K1H 8M5. E-mail: mharper{at}

      Received for publication 1 March 2002 and accepted in revised form 13 May 2002.

      M.-E.H., R.D., and R.M. contributed equally to this study.

      Δp, protonmotive force; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; RMR, resting metabolic rate; TRE, thyroid response element; UCP, uncoupling protein.

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