Pronounced adipogenesis and increased insulin sensitivity caused by overproduction of prostaglandin D2in vivo
Pronounced adipogenesis and increased insulin sensitivity caused by overproduction of prostaglandin D2in vivo
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DOI：
10.1111/j.1742-4658.2010.07565.x
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发表时间：
2010-03-01
期刊：
影响因子：
5.4
通讯作者：
Kawada, Teruo
中科院分区：
文献类型：
--
作者：
Fujitani, Yasushi;Aritake, Kosuke;Kawada, Teruo
脂质运载蛋白型前列腺素（PG）D合成酶在脂肪组织中表达，并参与2型糖尿病葡萄糖耐量和动脉粥样硬化的调节。然而，PGD（2）在体内脂肪形成中的生理作用尚不清楚，因为脂质运载蛋白型前列腺素D合酶也可以作为亲脂性分子（如类维生素A）的转运蛋白。我们建立了过表达人造血细胞PGDS（H-PGDS）的转基因（TG）小鼠，并研究了PGD（2）在脂肪形成中的体内功能。与野生型（WT）小鼠相比，H-PGDS TG小鼠白色脂肪组织中PGD（2）的产量增加了约7倍。在高脂肪饮食下，H-PGDS TG小鼠的体重增加比WT小鼠更多。与WT小鼠相比，H-PGDS TG小鼠血清瘦素和胰岛素水平升高，甘油三酯水平降低约50%。此外，在H-PGDS TG小鼠的白色脂肪组织中，过氧化物酶体增殖物激活受体γ、脂肪酸结合蛋白4和脂蛋白脂肪酶的转录水平与WT小鼠相比增加了约2倍至5倍。最后，H-PGDS TG小鼠在胰岛素钳夹后表现出明显的低血糖。这些结果表明，过度表达H-PGDS的TG小鼠在脂肪组织中大量产生PGD（2），导致明显的脂肪形成和胰岛素敏感性增加。本研究首次证明PGD（2）参与了体内脂肪细胞的分化和胰岛素敏感性的调节，H-PGDS TG小鼠有望成为糖尿病研究的新模型小鼠。
Lipocalin-type prostaglandin (PG) D synthase is expressed in adipose tissues and involved in the regulation of glucose tolerance and atherosclerosis in type 2 diabetes. However, the physiological roles of PGD(2) in adipogenesis in vivo are not clear, as lipocalin-type prostaglandin D synthase can also act as a transporter for lipophilic molecules, such as retinoids. We generated transgenic (TG) mice overexpressing human hematopoietic PGDS (H-PGDS) and investigated the in vivo functions of PGD(2) in adipogenesis. PGD(2) 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 gamma, 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 PGD(2) in adipose tissues, resulting in pronounced adipogenesis and increased insulin sensitivity. The present study provides the first evidence that PGD(2) participates in the differentiation of adipocytes and in insulin sensitivity in vivo, and the H-PGDS TG mice could constitute a novel model mouse for diabetes studies.