A Mitochondrial-Targeted Coenzyme Q Analog Prevents Weight Gain and Ameliorates Hepatic Dysfunction in High-Fat–Fed Mice

Abstract

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 mM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF-and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics.

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

“…A recent study of the anti-obesity effect of a mitochondria-targeting mitoQ, which can uncouple mitochondrial respiration in vitro , 39 did not reveal an increase in the metabolic rate of mitoQ-treated mice. 40 However, the study was performed in mice maintained at 22 °C, which could explain the lack of an effect of mitoQ on the metabolic rate of the mice.…”

“…Other mitochondria-targeting compounds such as mitoQ 40 and C 4 R1 (ref. 12) also influence food intake.…”

Angiotensin AT1A receptors on leptin receptor–expressing cells control resting metabolism

“…Body mass and food intake measurements and feces collection were done at the same time daily for 4 days. Energy per gram feces was determined by bomb calorimetry as previously described (48,49). This energy was applied to feces and food intake to determine energy intake and output, and thus caloric absorption.…”

Comprehensive Assessments of Energy Balance in Mice

“…– Parr Instrument Company, model 2817). We have used these models of equipment to examine digestive efficiency and energy efficiency in animals with manipulations of mitochondrial function and the gut microbiome [9,10] (Figure 3). …”