It was reported that mitochondrial aconitase was particularly susceptible to oxidative damage among those mitochondrial proteins because the electrophilicity of the fourth labile iron atom in its labile Fe-S cluster renders it especially sensitive to oxidative inactivation by nucleophilic superoxide anion. In addition, an aconitase inhibition-cascade was proposed to increase lipogenesis, slow lipolysis, increase feed intake, and decrease energy expenditure, which together resulted in obesity development. Therefore, combining the susceptibility of mitochondrial aconitase to oxidative damage with the above aconitase inhibition cascade, it was hypothesized in this study that oxidative stress contributed to obesity development by initiating the aconitase inhibition-cascade. We tested this hypothesis experimentally in two different fashions by using medium fat (MF) diet and mitochondrially targeted vitamin E (MitoVit E). Specifically, we hypothesized that MF diet contributes to obesity development by initiating the aconitase inhibition cascade, whereas MitoVit E can improve obesity development by reversing the aconitase inhibition cascade.

Sixty-four 7-week-old C57BL/6J male mice, after fed a high fat diet (60 kcal% from fat) for 5 weeks, were assigned randomly to 4 groups. Group I and III were fed a low fat diet (10 kcal% from fat) and a MF diet (32 kcal% from fat), respectively, with each group gavaged with drug vehicle (0.9% NaCl solution); Group II and IV were fed the same diets as Group I and II, respectively, with each group gavaged with 40 mg MitoVit E/kg body weight. Gavage was conducted every other day for 5 weeks. We showed that (1) oxidative stress is elevated with obesity development; (2) MitoVit E decreased MF diet-induced body weight gain (P < 0.05) without affecting feed intake; (3) MitoVit E decreased lipid deposition in liver (P < 0.001) and adipose tissues (P < 0.001) while increasing muscle mass (P < 0.05); (4) MitoVit E systemically decreased MF diet-induced oxidative stress indicated by a decrease of urinary isoprostane/creatinine; (5) MitoVit E acted in a tissue specific manner by decreasing mitochondrial H ₂O₂ production rate (P < 0.01), which attenuated the inhibition of aconitase activity (P < 0.05), increased protein oxidation (P < 0.01), and consequently increased ATP production rate (P < 0.05), only in liver, but not in muscle; (6) MitoVit E significantly increased the number and size of subsarcolemmal mitochondria in the soleus (P < 0.05); (7) MitoVit E upregulated gene expression of acyl-CoA oxidase in liver ( P < 0.05) and adipose tissue (P < 0.01) and carnitine palmitoyltransferase 1 in liver (P < 0.001), indicating MitoVit E enhanced peroxisomal and mitochondrial fatty acid oxidation. (8) MitoVit E, however, did not affect either those genes (such as fatty acid synthase and acetyl-CoA carboxylase) involved in lipogenesis in liver and adipose tissue or lipoprotein lipase involved in deposition of serum triacylglycerol in adipose tissue or hormone-sensitive lipase involved in lipolysis in adipose tissue.

Therefore, we concluded that (1) MitoVit E might play a role in energy partitioning by favoring elevated energy expenditure in adipose tissue and preserving energy storage in skeletal muscle; (2) MitoVit E decreases fat deposition in liver and white adipose tissue not by reversing “aconitase inhibition cascade” as we proposed, instead, through enhancing peroxisomal (in liver and adipose tissue) and mitochondrial (in liver) fatty acid oxidation. Taken together, all the evidence shown in our study indicates that MitoVit E merits additional research as an anti-obesity agent.