These authors contributed equally to this work.
Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice
Article first published online: 15 JUL 2009
© 2009 The Authors. Journal compilation © 2009 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd
Genes to Cells
Volume 14, Issue 8, pages 991–1001, August 2009
How to Cite
Inagaki, T., Tachibana, M., Magoori, K., Kudo, H., Tanaka, T., Okamura, M., Naito, M., Kodama, T., Shinkai, Y. and Sakai, J. (2009), Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. Genes to Cells, 14: 991–1001. doi: 10.1111/j.1365-2443.2009.01326.x
Communicated by: Masayuki Yamamoto (Tohoku University)
- Issue published online: 27 JUL 2009
- Article first published online: 15 JUL 2009
- Received: 10 March 2009 Accepted: 14 May 2009
Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing. Recent studies demonstrated that most covalent histone lysine modifications are reversible and the jumonji C (JmjC)-domain-containing proteins have been shown to possess such demethylase activities. However, there is little information available on the biological roles of histone lysine demethylation in intact animal model systems. JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) catalyses removal of H3K9 mono- and dimethylation through iron and α-ketoglutarate dependent oxidative reactions. Here, we demonstrate that JHDM2a also regulates metabolic genes related to energy homeostasis including anti-adipogenesis, regulation of fat storage, glucose transport and type 2 diabetes. Mice deficient in JHDM2a (JHDM2a−/−) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, which are hallmarks of metabolic syndrome. JHDM2a−/− mice furthermore exhibit fasted induced hypothermia indicating reduced energy expenditure and also have a higher respiratory quotient indicating less fat utilization for energy production. These observations may explain the obesity phenotype in these mice. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome.