Novel Mitochondrial Cationic Uncoupler C4R1 Is an Effective Treatment for Combating Obesity in Mice
A V Kalinovich1, I G Shabalina
1Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm, Sweden. anastasia.kalinovich@su.se.
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.
Insights
A novel compound, C4R1, significantly reduced food intake, body weight, and fat mass in obese mice by mildly uncoupling mitochondria. This suggests C4R1 as a promising therapeutic for obesity treatment.
Area of Science:
- Biochemistry
- Metabolic research
- Pharmacology
Background:
- Obesity presents significant health challenges with limited effective treatments.
- Mitochondrial uncoupling is a potential strategy for weight management.
Purpose of the Study:
- To investigate the anti-obesity effects of a novel cationic mitochondrial uncoupler, C4R1.
- To evaluate C4R1's efficacy in diet-induced obese mice.
Main Methods:
- Obesity was induced in C57Bl/6 mice using an eight-week high-fat diet.
- Mice received daily doses of C4R1 (30 and 12-14 µmol/kg) in drinking water for 30 days.
- Effects on food intake, body weight, fat mass, and respiratory quotient were measured.
Main Results:
- C4R1 treatment dose-dependently reduced food intake (by 68%), body weight (by 19%), and fat mass (by 21%) within six days at 30 µmol/kg.
- Weight loss was attributed to reduced food intake and increased metabolism via mitochondrial uncoupling.
- Improved lipid utilization was indicated by a decreased respiratory quotient.
- The classical uncoupler 2,4-dinitrophenol showed no effect at a similar dose.
Conclusions:
- C4R1 demonstrates significant anti-obesity effects in mice.
- Mild mitochondrial uncoupling by C4R1 is a viable therapeutic strategy for obesity.
- Further research into C4R1 for obesity treatment is warranted.
