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Novel mitochondrial cationic uncoupler C4R1 is an effective treatment for combating obesity in mice

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Abstract

Obesity is associated with premature mortality, impaired quality of life, and large healthcare costs. However, treatment options remain quite limited. Here we studied potential anti-obesity effects of a novel cationic mitochondrial uncoupler, C4R1 (derivative of rhodamine 19) in C57Bl/6 mice. Obesity was induced by long-term (eight weeks) high fat diet feeding at thermoneutrality. The treated group of mice received consecutively two doses of C4R1 in drinking water (30 and 12–14 μmol/kg daily) during 30 days. Effects of C4R1 were dose-dependent. After six days of C4R1 treatment at dose 30 μmol/kg daily, food intake was reduced by 68%, body weight by 19%, and fat mass by 21%. Body weight decrease was explained partly by reduced food intake and partly by increased metabolism, likely resulting from uncoupling. Body fat reduction upon C4R1 treatment was associated with improved lipid utilization estimated from decrease in respiratory quotient to the minimal level (0.7). Interestingly, the classical uncoupler 2,4-dinitrophenol at similar dose (27 μmol/kg daily) did not have any effect. Our results are relevant to the search for substances causing mild uncoupling of mitochondria that could be a promising therapeutic strategy to treat obesity.

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Abbreviations

C4R1:

a short-chain alkyl derivative of rhodamine 19

DNP:

2,4-dinitrophenol

MRI:

magnetic resonance imaging

RMR:

resting metabolic rate

RQ:

respiratory quotient

UCP1:

uncoupling protein 1

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Authors and Affiliations

  1. Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm, Sweden

    A. V. Kalinovich & I. G. Shabalina

  2. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    A. V. Kalinovich & I. G. Shabalina

Authors
  1. A. V. Kalinovich
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  2. I. G. Shabalina
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Correspondence to A. V. Kalinovich.

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Published in Russian in Biokhimiya, 2015, Vol. 80, No. 5, pp. 735–745.

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Kalinovich, A.V., Shabalina, I.G. Novel mitochondrial cationic uncoupler C4R1 is an effective treatment for combating obesity in mice. Biochemistry Moscow 80, 620–628 (2015). https://doi.org/10.1134/S0006297915050156

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  • DOI: https://doi.org/10.1134/S0006297915050156

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