Mitochondrial proton leak in obesity-resistant and obesity-prone mice.
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.
Fink
Brian D
BD
University of Iowa, Iowa City Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
Herlein
Judy A
JA
Almind
Katrine
K
Cinti
Saverio
S
Kahn
C Ronald
CR
Sivitz
William I
WI
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D004032:Diet; D066298:In Vitro Techniques; D007473:Ion Channels / Q000096:biosynthesis / Q000235:genetics; D007700:Kinetics; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D011522:Protons; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013045:Species Specificity; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3
D007473:Ion Channels; D020738:Leptin; D024101:Mitochondrial Proteins; D011522:Protons; D012333:RNA, Messenger; C000604372:Ucp1 protein, mouse; C000604393:Ucp3 protein, mouse; D000071256:Uncoupling Protein 1; D000071247:Uncoupling Protein 3