Imai Takeshi, Takakuwa Reiko, Marchand Sandra, Dentz Emilie, Bornert Jean-Marc, Messaddeq Nadia, Wendling Olivia, Mark Manuel, Desvergne Béatrice, Wahli Walter, Chambon Pierre, Metzger Daniel
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, BP10142, 1 Rue Laurent Fries, 67404 Illkirch, France.
Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4543-7. doi: 10.1073/pnas.0400356101. Epub 2004 Mar 16.
The peroxisome proliferator-activated receptor gamma (PPARgamma) mediates the activity of the insulin-sensitizing thiazolidinediones and plays an important role in adipocyte differentiation and fat accretion. The analysis of PPARgamma functions in mature adipocytes is precluded by lethality of PPARgamma(-/-) fetuses and tetraploid-rescued pups. Therefore we have selectively ablated PPARgamma in adipocytes of adult mice by using the tamoxifen-dependent Cre-ER(T2) recombination system. We show that mature PPARgamma-null white and brown adipocytes die within a few days and are replaced by newly formed PPARgamma-positive adipocytes, demonstrating that PPARgamma is essential for the in vivo survival of mature adipocytes, in addition to its well established requirement for their differentiation. Our data suggest that potent PPARgamma antagonists could be used to acutely reduce obesity.
过氧化物酶体增殖物激活受体γ(PPARγ)介导胰岛素增敏噻唑烷二酮类药物的活性,并在脂肪细胞分化和脂肪蓄积中发挥重要作用。PPARγ(-/-)胎儿和四倍体拯救幼崽的致死性使得对成熟脂肪细胞中PPARγ功能的分析受到限制。因此,我们通过使用他莫昔芬依赖性Cre-ER(T2)重组系统,在成年小鼠的脂肪细胞中选择性地敲除了PPARγ。我们发现,成熟的PPARγ缺失的白色和棕色脂肪细胞在几天内死亡,并被新形成的PPARγ阳性脂肪细胞所取代,这表明PPARγ除了对成熟脂肪细胞的分化有既定的需求外,对其体内存活也是必不可少的。我们的数据表明,强效的PPARγ拮抗剂可用于急性减轻肥胖。