Abstract 15429: Decrease in Mitochondorial Atp5j Causes the Enhanced Activity of Uncoupling Protein 1 Leading to Increased Heat Generation and Reduced Fat Accumulation
Mitochondrial ATP synthase generates ATP by utilizing a proton gradient. Uncoupling proteins (UCPs) in the inner mitochondrial membrane uncouple the proton gradient from ATP synthesis. In brown adipose tissue (BAT), the proton gradient is mostly released as heat through the UCP1. We recently showed that ATP5J, one of the subunits of the ATP synthase, is released into the circulation as a vasoconstrictor. However, the role of ATP5J in obesity remains unclear. We generated mice lacking the ATP5J gene. The ATP5J-null homozygous mice are lethal before E10.5. The heterozygous male mice (Het) had a slightly reduced body weight (BW) compared with their wild-type littermates (WT) at 6 months old on a normal chow (NC), and was resistant to obesity induced by high-fat diet (HFD). The Het mice had a reduced total adipose tissue evaluated by MRI compared with the WT mice on a NC (6.9±0.4 vs 10.2±1.2 %BW, n=7, p<0.05) and on a HFD (24.8±2.5 vs 33.2±1.7 %BW, n=7, p<0.05). Heat production assessed by indirect calorymetry was higher in the Het than in the WT mice on both NC and HFD despite the similar degrees of food consumption and physical activity. The UCP1 gene expression in BAT of the Het mice was enhanced by 2.2±0.5-fold compared with the WT mice on a NC (n=7, p<0.05). The mitochondrial membrane potential in the Het mouse embryonic fibroblasts (MEF) was significantly enhanced by 22% compared with the WT-MEF evaluated by flow cytometry using the fluorescent dye (TMRM). Moreover, cellular reactive oxygen species (ROS) levels measured by oxidation of 2’-7’-dichlorofluorescein diacetate were significantly higher in the Het-MEF than in the WT-MEF (26.3±0.8 vs 21.9±0.3 nM, n=8, p<0.05). Consistent with this, plasma levels of thiobarbituric acid-reactive substances (TBARS), an oxidative stress marker, were significantly higher in the Het than in the WT mice (16.7±1.6 vs 12.0±1.2 μM, n=6-8, p<0.05). Electron microscopic analysis revealed structural abnormalities of mitochondria in BAT of the Het mice such as reduced cristae density. Also, the ATP content in BAT of the Het mice was decreased to 65% of WT mice (n=4-5, p<0.05). These findings indicate that decrease in mitochondorial ATP5J causes the enhanced activity of UCP1 leading to increased heat generation and reduced fat accumulation.
- © 2012 by American Heart Association, Inc.