Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue

Abstract

Obesity: Possible protective enzyme identified An enzyme that limits the build-up of reactive oxygen species (ROS) in fat cells protects mice against metabolic stress during a high-fat diet. Calorie overload leads to high levels of damaging ROS in the mitochondria of brown fat cells. This can disrupt processes that regulate energy expenditure and glucose metabolism. A team led by Seung-Soon Im at Keimyung University, Daegu, South Korea, and Timothy F. Osborne at Johns Hopkins University, St. Petersburg, USA, examined the role of an enzyme called isocitrate dehydrogenase 2 (IDH2), which is known to regulate the build-up of mitochondrial ROS. In mice fed a high-fat diet, those without IDH2 experienced accelerated weight gain, triggered by increased ROS levels and decreased mitochondrial function. A dose of an antioxidant in the diet reduced this effect, suggesting that patients with obesity may benefit from antioxidant supplements. Isocitrate dehydrogenase 2 (IDH2) is an NADP(+)-dependent enzyme that catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutarate in the mitochondrial matrix, and is critical for the production of NADPH to limit the accumulation of mitochondrial reactive oxygen species (ROS). Here, we showed that high-fat diet (HFD) feeding resulted in accelerated weight gain in the IDH2KO mice due to a reduction in whole-body energy expenditure. Moreover, the levels of NADP(+), NADPH, NAD(+), and NADH were significantly decreased in the brown adipose tissue (BAT) of the HFD-fed IDH2KO animals, accompanied by decreased mitochondrial function and reduced expression of key genes involved in mitochondrial biogenesis, energy expenditure, and ROS resolution. Interestingly, these changes were partially reversed when the antioxidant butylated hydroxyanisole was added to the HFD. These observations reveal a crucial role for IDH2 in limiting ROS-dependent mitochondrial damage when BAT metabolism is normally enhanced to limit weight gain in response to dietary caloric overload.