Tài liệu Báo cáo khoa học: RMI1 deficiency in mice protects from diet and genetic-induced obesity

RMI1 deficiency in mice protects from diet and

genetic-induced obesity

Akira Suwa1

, Masayasu Yoshino2

, Chihiro Yamazaki3

, Masanori Naitou2

, Rie Fujikawa3

,

Shun-ichiro Matsumoto2

, Takeshi Kurama1

, Teruhiko Shimokawa1 and Ichiro Aramori2

1 Pharmacology Research Labs, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

2 Molecular Medicine Labs, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan

3 Trans Genic Inc., Chuo-ku, Tokyo, Japan

Introduction

Obesity is a complex disorder and a major risk factor

for metabolic diseases such as type 2 diabetes mellitus,

hypertension and cardiovascular disease. This energy

balance disorder is controlled by multiple pathways.

Several genes are known to be responsible for obesity:

the genes obese (ob) [1], fat (fa) [2], agouti (ay) [3],

tubby (tub) [4] and diabetes (db) [5] have been identified

and characterized in genetically obese models.

However, other important molecules involved in the

regulation of energy homeostasis have yet to be

identified.

The exchangeable gene trap method is a powerful

strategy that could be used to locate single-gene defects

responsible for energy homeostasis disorders [6]. With

this method, it is possible to mutate the mouse genome

randomly on a large scale, and then isolate and

identify the mutated gene. Several other genes have

been identified by this method [7–9]. In this study, we

Keywords

E2F; energy homeostasis; gene trap;

high-fat diet; obesity; RMI1

Correspondence

A. Suwa, Department of Metabolic

Diseases, Pharmacology Research Labs,

Drug Discovery Research, Astellas Pharma

Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki

305-8585, Japan

Fax: +81 29 852 5391

Tel: +81 29 863 6417

E-mail: [email protected]

(Received 2 September 2009, revised 19

November 2009, accepted 24 November

2009)

doi:10.1111/j.1742-4658.2009.07513.x

The aim of this study is to discover and characterize novel energy homeo￾stasis-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 gen￾ome 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

(Ay

) gene. Endogenous RMI1 genes were found to be up-regulated in the

liver and adipose tissue of KK-Ay 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 mole￾cule, was suppressed in the mutant mice. These results suggest that the reg￾ulation of energy balance by RMI1 is attributable to the regulation of food

intake and E2F8 expression in adipose tissue. Taken together, these find￾ings demonstrate that RMI1 is a novel molecule that regulates energy

homeostasis.

Abbreviations

AUC, area under the curve; Ay

, lethal yellow agouti; BLM, Bloom syndrome; RMI1, recQ-mediated genome instability 1.

FEBS Journal 277 (2010) 677–686 ª 2009 The Authors Journal compilation ª 2009 FEBS 677