Download Role of IDH2 in the brown adipose tissue Abstract

Role of IDH2 in the brown adipose tissue
Abstract
Brown adipose tissue (BAT) plays a key role in controlling energy expenditure and
thermogenesis by fatty acid oxidation (FAO) in mitochondria. Accumulation of
oxidative stress in adipose tissue is one of the early events in the development of
metabolic syndrome in obesity. Nonetheless, a cause and effect relationship between
oxidative stress and obesity is not well understood. Isocitrate dehydrogenase 2 (IDH2)
is a NADP+-dependent isocitrate dehydrogenase which is located in the mitochondria
and catalyzes the oxidative decarboxylation of isocitrate to -ketoglutarate. Even
though IDH2 is involved in intermediary metabolism and decrease of reactive oxygen
species (ROS), there is currently a limited understanding of how IDH2 ameliorates
ROS-based obesity at the molecular level. Here, we describe the function of IDH2 in
high fat diet-induced obesity. IDH2 knockout (KO) mice showed reduction of energy
expenditure and FAO, resulting in increase of fat mass. Moreover, IDH2 KO mice
exhibited significantly elevated level of NADP+/NADPH as well as NAD+/NADH ratio
in BAT. And ROS production was increased in IDH2 KO cells, suggesting that loss of
IDH2 induces BAT dysfunction owing to inhibition of ROS-scavenging system. In
summary, the present study showed that deficiency of IHD2 leads to mitochondrial
dysfunction and increased ROS production, resulting in decrease of FAO and increase
of energy imbalance. These data demonstrate a previously unrecognized contribution
of IDH2 to ROS-mediated obesity.