Mitochondria-targeted dodecyltriphenylphosphonium (C(12)TPP) combats high-fat-diet-induced obesity in mice

BACKGROUND: A membrane-penetrating cation, dodecyltriphenylphosphonium (C(12)TPP), facilitates the recycling of fatty acids in the artificial lipid membrane and mitochondria. C(12)TPP can dissipate mitochondrial membrane potential and may affect total energy expenditure and body weight in animals and humans. METHODS: We investigated the metabolic effects of C(12)TPP 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. RESULTS: In mice, C(12)TPP (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. C(12)TPP did not affect water palatability and intake or the energy and lipid content in feces. The addition of C(12)TPP to isolated brown-fat mitochondria resulted in increased oxygen consumption. Three hours of pretreatment with C(12)TPP also increased oligomycin-insensitive oxygen consumption in brown adipocyte cultures (P<0.01). The effects of C(12)TPP on mitochondria, cells and mice were independent of uncoupling protein 1 (UCP1). However, C(12)TPP 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 C(12)TPP-treated mice was due to reduced food intake. C(12)TPP treatment elevated the resting metabolic rate (RMR) by up to 18% (P<0.05) compared with pair-fed animals. C(12)TPP reduced the respiratory exchange ratio, indicating enhanced fatty acid oxidation in mice. CONCLUSIONS: C(12)TPP combats diet-induced obesity by reducing food intake, increasing the RMR and enhancing fatty acid oxidation.