Novel Mitochondrial Cationic Uncoupler C₄R1 Is an Effective Treatment for Combating Obesity in Mice

---

A. V. Kalinovich^1,2* and I. G. Shabalina^1,2

¹Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm, Sweden; fax: +46 (8) 164209; E-mail: anastasia.kalinovich@su.se; irina.shabalina@su.se

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

^* To whom correspondence should be addressed.

Received January 19, 2015; Revision received January 30, 2015

---

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.

---

KEY WORDS: cationic mitochondrial uncoupler, 2,4-dinitrophenol, obesity, resting metabolic rate, energy expenditure

DOI: 10.1134/S0006297915050156

---