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

Jae Ho Lee, Younghoon Go, Do Young Kim, Sun Hee Lee, Ok Hee Kim, Yong Hyun Jeon, Taeg Kyu Kwon, Jae Hoon Bae, Dae Kyu Song, Im Joo Rhyu, In Kyu Lee, Minho Shong, Byung Chul Oh, Christopher Petucci, Jeen Woo Park, Timothy F. Osborne, Seung Soon Im

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Isocitrate dehydrogenase 2 (IDH2) is an NADP+-dependent enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-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.

Original languageEnglish
Pages (from-to)238-252
Number of pages15
JournalExperimental and Molecular Medicine
Volume52
Issue number2
DOIs
Publication statusPublished - 2020 Feb 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

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