Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice.
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 alpha-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.
Inagaki
Takeshi
T
Metabolism and Endocrinology Division, Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
Tachibana
Makoto
M
Magoori
Kenta
K
Kudo
Hiromi
H
Tanaka
Toshiya
T
Okamura
Masashi
M
Naito
Makoto
M
Kodama
Tatsuhiko
T
Shinkai
Yoichi
Y
Sakai
Juro
J
D016475:3T3 Cells; D017667:Adipocytes; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004734:Energy Metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006706:Homeostasis; D056484:Jumonji Domain-Containing Histone Demethylases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000235:genetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism; D010641:Phenotype
D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; C511045:Kdm3a protein, mouse; D010089:Oxidoreductases, N-Demethylating