Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice

Abstract

We recently reported that mitoquinone (mitoQ, 500 μmol/L) added to drinking water of C57BL/6J mice attenuated weight gain, decreased food intake, increased hypothalamic orexigenic gene expression, and mitigated oxidative stress when administered from the onset of high‐fat (HF) feeding. Here, we examined the effects of mitoQ on pre‐existing obesity in C57BL/6J mice first made obese by 107 days of HF feeding. In contrast to our preventative study, we found that already obese mice did not tolerate mitoQ at 500 μmol/L. Within 4 days of administration, obese mice markedly decreased food and water intake and lost substantial weight necessitating a dose reduction to 250 μmol/L. Food and water intake then improved. Over the next 4 weeks, body mass of the mitoQ‐treated mice increased faster than vehicle‐treated controls but did not catch up. Over the subsequent 10 weeks, weights of the mitoQ‐treated group remained significantly less than vehicle control, but percent fat and food intake did not differ. Although the mitoQ‐treated groups continued to drink less, there was no difference in percent body fluid and no laboratory evidence of dehydration at study end. At the time of killing, hypothalamic NPY gene expression was reduced in the mitoQ‐treated mice . Liver fat was markedly increased by HF feeding but did not differ between mitoQ and vehicle groups and, in contrast to our previous preventative study, there was no improvement in plasma alanine amino transferase or liver hydroperoxides. In summary, administration of mitoQ to already obese mice attenuated weight gain, but showed limited overall benefit.

Effect of a mitochondrial‐targeted coenzyme Q analog on pancreatic β‐cell function and energetics in high fat fed obese mice

“…As shown in Figure A and B, food intake was mildly but not significantly reduced in the mitoQ‐ compared to vehicle‐treated mice. Consistent with past reports by ourselves and others, water intake by the mitoQ‐treated mice was reduced (Figure C and D).…”

“…Our current results are largely consistent with our past studies of the action of mitoQ on HF‐fed mice. In both this study and in past reports we found that mitoQ improved energy expenditure (based on gas respiratory exchange) and decreased food intake. However, in our past reports, unlike the present, the effect on whole body respiration was short of significance.…”

“…Because available drug therapy is, at best, only partially effective and associated with side effects, continued efforts are underway to develop new pharmacologic approaches. In recent studies, we and others have found that mitoQ administered to obesity prone mice mitigates weight gain acting by decreasing appetite and/or increasing energy expenditure, the latter likely due to mild respiratory uncoupling.…”

“…MitoQ may also suppress appetite and increase insulin sensitivity, suggesting action as an antiobesity and/ or antidiabetic agent. Indeed, we and others [7][8][9] have administered mitoQ to obese or obesity prone mice and found that the compound decreased weight and fat mass and also reduced hepatic oxidative damage due to steatosis. 8 In contrast with what is known of the action of mitoQ in obesity and insulin resistant states, little is known regarding the effect of mitoQ on pancreatic islet function.…”

“…MitoQ may also suppress appetite and increase insulin sensitivity, suggesting action as an antiobesity and/or antidiabetic agent. Indeed, we and others have administered mitoQ to obese or obesity prone mice and found that the compound decreased weight and fat mass and also reduced hepatic oxidative damage due to steatosis …”