title: Increased obesity resistance and insulin sensitivity in mice lacking the isocitrate dehydrogenase 2 gene.
abstract: Reactive oxygen species (ROS) are a byproduct of normal metabolism and play important roles in cell signaling and homeostasis. Mitochondria, the main organelles involved in intracellular ROS production, play central roles in modulating redox-dependent cellular processes such as metabolism and apoptosis. We recently reported an important role for mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) in cellular redox regulation. Here, we show that mice with targeted disruption of IDH2 exhibit resistance to obesity, with lower body weight and reduced visceral fat, and increased insulin sensitivity accompanied by enhanced energy expenditure relative to controls. This function of IDH2 is linked to its capacity to suppress lipogenesis in visceral adipose tissue, partly via transcriptional repression of SREBP1, and to increase thermogenesis in adipocytes by transcriptional activation of UCP1 via activation of the p38 signaling axis. Our results highlight the importance of redox balance in the regulation of metabolism and demonstrate that IDH2 plays a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing this protein as a potential therapeutic target in the treatment of type 2 diabetes and obesity.
authors: School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea.
authors: Su Jeong
authors: SJ
authors: Lee
authors: School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea.
authors: Sung Hwan
authors: SH
authors: Kim
authors: Department of Anatomy, School of Medicine, Kyungpook National University, Taegu, Republic of Korea.
authors: Kwon Moo
authors: KM
authors: Park
authors: Department of Food and Biotechnology, Korea University, Sejong, Republic of Korea; Institutes of Natural Sciences, Korea University, Sejong, Republic of Korea. Electronic address: jinhyuplee@korea.ac.kr.
authors: Jin Hyup
authors: JH
authors: Lee
authors: School of Life Sciences and Biotechnology, BK21 Plus KNU Creative BioResearch Group, College of Natural Sciences, Kyungpook National University, Taegu, Republic of Korea. Electronic address: parkjw@knu.ac.kr.
authors: Jeen-Woo
authors: JW
authors: Park
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D004734:Energy Metabolism / Q000235:genetics; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D022722:Thermogenesis / Q000235:genetics; D000071256:Uncoupling Protein 1 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Isocitrate dehydrogenase 2; Obesity; Reactive oxygen species