Tài liệu Báo cáo khoa học: Pronounced adipogenesis and increased insulin sensitivity caused by

Pronounced adipogenesis and increased insulin sensitivity

caused by overproduction of prostaglandin D2 in vivo

Yasushi Fujitani1,*, Kosuke Aritake1

, Yoshihide Kanaoka1,2, Tsuyoshi Goto3

, Nobuyuki Takahashi3

,

Ko Fujimori1,4 and Teruo Kawada3

1 Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Japan

2 Department of Medicine, Harvard Medical School, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital,

Boston, MA, USA

3 Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University,

Japan

4 Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Japan

Introduction

The amount of adipose tissue in the body is an impor￾tant factor in the maintenance of energy balance,

through its ability to store and release fat, and is

altered in various physiological or pathological condi￾tions [1]. The increased adipose tissue mass associated

with obesity results from an increase in the number

Keywords

adipocytes; H-PGDS; obesity; PGD2;

transgenic mouse

Correspondence

K. Fujimori, Laboratory of Biodefense and

Regulation, Osaka University of

Pharmaceutical Sciences, 4-20-1 Nasahara,

Takatsuki, Osaka 569-1094, Japan

Fax: +81 726 690 1055

Tel: +81 726 690 1055

E-mail: [email protected]

*Present address

Pharmaceutical Research Division, Takeda

Pharmaceutical Co. Ltd., Osaka, Japan

(Received 28 October 2009, revised 22

December 2009, accepted 4 January

2010)

doi:10.1111/j.1742-4658.2010.07565.x

Lipocalin-type prostaglandin (PG) D synthase is expressed in adipose

tissues and involved in the regulation of glucose tolerance and atherosclero￾sis in type 2 diabetes. However, the physiological roles of PGD2 in adipo￾genesis in vivo are not clear, as lipocalin-type prostaglandin D synthase can

also act as a transporter for lipophilic molecules, such as retinoids. We gen￾erated transgenic (TG) mice overexpressing human hematopoietic PGDS

(H-PGDS) and investigated the in vivo functions of PGD2 in adipogenesis.

PGD2 production in white adipose tissue of H-PGDS TG mice was

increased approximately seven-fold as compared with that in wild-type

(WT) mice. With a high-fat diet, H-PGDS TG mice gained more body

weight than WT mice. Serum leptin and insulin levels were increased in

H-PGDS TG mice, and the triglyceride level was decreased by about 50%

as compared with WT mice. Furthermore, in the white adipose tissue of

H-PGDS TG mice, transcription levels of peroxisome proliferator-activated

receptor c, fatty acid binding protein 4 and lipoprotein lipase were

increased approximately two-fold to five-fold as compared with those of

WT mice. Finally, H-PGDS TG mice showed clear hypoglycemia after

insulin clamp. These results indicate that TG mice overexpressing H-PGDS

abundantly produced PGD2 in adipose tissues, resulting in pronounced adi￾pogenesis and increased insulin sensitivity. The present study provides the

first evidence that PGD2 participates in the differentiation of adipocytes

and in insulin sensitivity in vivo, and the H-PGDS TG mice could consti￾tute a novel model mouse for diabetes studies.

Abbreviations

15d-PGJ2, 15-deoxy-D12,14 prostaglandin J2; ACC, acetyl-CoA carboxylase; aP2, fatty acid-binding protein 4, adipocyte; BAT, brown adipose

tissue; CMV, cytomegalovirus; CT, computed tomography; DEX, dexamethasone; GST, glutathione S-transferase; HF, high-fat; H-PGDS,

hematopoietic prostaglandin D synthase; IBMX, 3-isobutyl-1-methylxanthine; L-PGDS, lipocalin-type prostaglandin D synthase; LPL,

lipoprotein lipase; PG, prostaglandin; PGDS, prostaglandin D synthase; PPAR, peroxisome proliferator-activated receptor; SCD, stearoyl-CoA

desaturase; SEM, standard error of the mean; TG, transgenic; WAT, white adipose tissue.

1410 FEBS Journal 277 (2010) 1410–1419 ª 2010 The Authors Journal compilation ª 2010 FEBS