RMI1 deficiency in mice protects from diet and genetic-induced obesity.
The aim of this study is to discover and characterize novel energy homeostasis-related molecules. We screened stock mouse embryonic stem cells established using the exchangeable gene trap method, and examined the effects of deficiency of the target gene on diet and genetic-induced obesity. The mutant strain 0283, which has an insertion at the recQ-mediated genome instability 1 (RMI1) locus, possesses a number of striking features that allow it to resist metabolic abnormalities. Reduced RMI1 expression, lower fasting-blood glucose and a reduced body weight (normal diet) were observed in the mutant mice. When fed a high-fat diet, the mutant mice were resistant to obesity, and also showed improved glucose intolerance and reduced abdominal fat tissue mass and food intake. In addition, the mutants were also resistant to obesity induced by the lethal yellow agouti (A(y)) gene. Endogenous RMI1 genes were found to be up-regulated in the liver and adipose tissue of KK-A(y) mice. RMI1 is a component of the Bloom's syndrome gene helicase complex that maintains genome integrity and activates cell-cycle checkpoint machinery. Interestingly, diet-induced expression of E2F8 mRNA, which is an important cell cycle-related molecule, was suppressed in the mutant mice. These results suggest that the regulation of energy balance by RMI1 is attributable to the regulation of food intake and E2F8 expression in adipose tissue. Taken together, these findings demonstrate that RMI1 is a novel molecule that regulates energy homeostasis.
Suwa
Akira
A
Department of Metabolic Diseases, Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. akira.suwa@jp.astellas.com
Yoshino
Masayasu
M
Yamazaki
Chihiro
C
Naitou
Masanori
M
Fujikawa
Rie
R
Matsumoto
Shun-Ichiro
S
Kurama
Takeshi
T
Shimokawa
Teruhiko
T
Aramori
Ichiro
I
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control; D012097:Repressor Proteins / Q000235:genetics; D015854:Up-Regulation
D001786:Blood Glucose; C504722:E2F8 protein, mouse; D012097:Repressor Proteins