Mitochondrial proton leak in obesity-resistant and obesity-prone mice

1 University of Iowa and the Iowa City Veterans Affairs Medical Center, Iowa City, Iowa; 2 Novo Nordisk A/S, Novo Nordisk Park, Måløv, Denmark; 3 Institute of Normal Human Morphology-Anatomy, University of Ancona, Ancona, Italy; and 4 Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts Submitted 2 July 2007 ; accepted in final form 22 August 2007 We quantified uncoupling proteins (UCPs) in molar amounts and assessed proton conductance in mitochondria isolated from interscapular brown adipose tissue (IBAT) and hindlimb muscle [known from prior work to contain ectopic brown adipose tissue (BAT) interspersed between muscle fibers] of obesity-resistant 129S6/SvEvTac (129) and obesity-prone C57BL/6 (B6) mice under conditions of low (LF) and high-fat (HF) feeding. With usual feeding, IBAT mitochondrial UCP1 content and proton conductance were greater in 129 mice than B6. However, with HF feeding, UCP1 and proton conductance increased more in B6 mice. Moreover, with HF feeding GDP-inhibitable proton conductance, specific for UCP1, equaled that seen in the 129 strain. UCP1 expression was substantial in mitochondria from hindlimb muscle tissue (ectopic BAT) of 129 mice as opposed to B6 but did not increase with HF feeding in either strain. As expected, muscle UCP3 expression increased with HF feeding in both strains but did not differ by strain. Moreover, the proton conductance of mitochondria isolated from hindlimb muscle tissue did not differ by strain or diet. Our data uncover a response to weight gain in obesity-prone (compared to resistant) mice unrecognized in prior studies that examined only UCP1 mRNA. Obesity-prone mice have the capacity to increase both IBAT UCP1 protein and mitochondrial proton conductance as much or more than obesity-resistant mice. But, this is only achieved only at a higher body mass and, therefore, may be adaptive rather than preventative. Neither obesity-prone nor resistant mice respond to HF feeding by expressing more UCP1 in ectopic BAT within muscle tissue. uncoupling protein; mitochondria; obesity Address for reprint requests and other correspondence: W. Sivitz, Dept. of Internal Medicine, Division of Endocrinology and Metabolism, Univ. of Iowa Hospitals and Clinics, 422GH, 200 Hawkins Dr., Iowa City, IA. 52242 (e-mail: william-sivitz{at}uiowa.edu )