A dominant negative peroxisome proliferator-activated receptor-γ knock-in mouse exhibits features of the metabolic syndrome
A dominant negative peroxisome proliferator-activated receptor-γ knock-in mouse exhibits features of the metabolic syndrome
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DOI：
10.1074/jbc.m407539200
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发表时间：
2005-04-29
影响因子：
4.8
通讯作者：
Jameson, JL
中科院分区：
文献类型：
--
作者：
Freedman, BD;Lee, EJ;Jameson, JL
过氧化物酶体增殖物激活受体-γ（PPAR-gamma）是核激素受体家族的一员，是脂肪生成的主要调节因子。具有显性负性PPAR γ突变的人具有代谢综合征的特征（严重胰岛素抵抗、血脂异常和高血压）。我们建立了一个敲入小鼠模型，其中含有一个有效的显性负性PPAR γ L466 A突变，该突变先前显示在体外抑制野生型PPAR γ作用。纯合子PPAR γ L466 A基因敲入小鼠在子宫内死亡。杂合子PPAR γ L466 A基因敲入（PPARKI）小鼠表现出脂肪细胞发育不良、低脂联素血症、血清游离脂肪酸增加和肝脂肪变性。当进行高脂肪饮食喂养时，PPARKI小鼠的体重增加显著低于对照组。PPARKI小鼠的高胰岛素-正葡萄糖钳夹研究显示胰岛素抵抗和骨骼肌葡萄糖摄取减少。雌性PPARKI小鼠表现出与饮食无关的高血压。PPARKI小鼠为研究受损的PPAR γ功能与代谢综合征之间的关系提供了一种新的模型。
Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a member of the nuclear hormone receptor family, is a master regulator of adipogenesis. Humans with dominant negative PPAR gamma mutations have features of the metabolic syndrome ( severe insulin resistance, dyslipidemia, and hypertension). We created a knock-in mouse model containing a potent dominant negative PPAR gamma L466A mutation, shown previously to inhibit wild-type PPAR gamma action in vitro. Homozygous PPAR gamma L466A knock-in mice die in utero. Heterozygous PPAR gamma L466A knock-in (PPARKI) mice exhibit hypoplastic adipocytes, hypoadiponectinemia, increased serum-free fatty acids, and hepatic steatosis. When subjected to high fat diet feeding, PPARKI mice gain significantly less weight than controls. Hyperinsulinemic-euglycemic clamp studies in PPARKI mice revealed insulin resistance and reduced glucose uptake into skeletal muscle. Female PPARKI mice exhibit hypertension independent of diet. The PPARKI mouse provides a novel model for studying the relationship between impaired PPAR gamma function and the metabolic syndrome.