Mitochondria-targeted dodecyltriphenylphosphonium (C₁₂TPP) combats high-fat-diet-induced obesity in mice.

Abstract

A membrane-penetrating cation, dodecyltriphenylphosphonium (C₁₂TPP), facilitates the recycling of fatty acids in the artificial lipid membrane and mitochondria. C₁₂TPP can dissipate mitochondrial membrane potential and may affect total energy expenditure and body weight in animals and humans. We investigated the metabolic effects of C₁₂TPP in isolated brown-fat mitochondria, brown adipocyte cultures and mice in vivo. Experimental approaches included the measurement of oxygen consumption, carbon dioxide production, western blotting, magnetic resonance imaging and bomb calorimetry. In mice, C₁₂TPP (50 μmol per (day•kg body weight)) in the drinking water significantly reduced body weight (12%, P<0.001) and body fat mass (24%, P<0.001) during the first 7 days of treatment. C₁₂TPP did not affect water palatability and intake or the energy and lipid content in feces. The addition of C₁₂TPP to isolated brown-fat mitochondria resulted in increased oxygen consumption. Three hours of pretreatment with C₁₂TPP also increased oligomycin-insensitive oxygen consumption in brown adipocyte cultures (P<0.01). The effects of C₁₂TPP on mitochondria, cells and mice were independent of uncoupling protein 1 (UCP1). However, C₁₂TPP treatment increased the mitochondrial protein levels in the brown adipose tissue of both wild-type and UCP1-knockout mice. Pair-feeding revealed that one-third of the body weight loss in C₁₂TPP-treated mice was due to reduced food intake. C₁₂TPP treatment elevated the resting metabolic rate (RMR) by up to 18% (P<0.05) compared with pair-fed animals. C₁₂TPP reduced the respiratory exchange ratio, indicating enhanced fatty acid oxidation in mice. C₁₂TPP combats diet-induced obesity by reducing food intake, increasing the RMR and enhancing fatty acid oxidation.