Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy
Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy
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DOI：
10.1101/gad.12.20.3182
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发表时间：
1998-10-15
影响因子：
10.5
通讯作者：
Brown, MS
中科院分区：
文献类型：
--
作者：
Shimomura, I;Hammer, RE;Brown, MS
在培养的3T3-L1前脂肪细胞中过表达核型固醇调节元件结合蛋白-1c(nSREBP-1c/Add1)可以促进脂肪细胞的分化。在这里，我们获得了在脂肪细胞特异性aP2增强子/启动子控制下在脂肪组织中过表达nSREBP-1c的转基因小鼠。该综合征具有以下特点：(1)脂肪组织分化紊乱。白脂未能充分分化，白脂库的大小明显缩小。棕色脂肪肥大，含有类似未成熟白色脂肪的富含脂肪的细胞。脂肪细胞分化标志物(C/EBPα、PPAR-γ、脂蛋白、瘦素、UCP1)的mRNA水平降低，Pref-1、TNFα水平升高。(2)明显的胰岛素抵抗，血浆胰岛素升高60倍。(3)血糖升高的糖尿病(>；300 mg/dl)，注射胰岛素后仍未下降。(4)出生后脂肪肝和晚年血浆甘油三酯水平升高。这些小鼠表现出先天性泛发性脂肪营养不良症(CGL)的许多特征，CGL是人类的一种常染色体隐性遗传病。
Overexpression of the nuclear form of sterol regulatory element-binding protein-lc (nSREBP-1c/ADD1) in cultured 3T3-L1 preadipocytes was shown previously to promote adipocyte differentiation. Here, we produced transgenic mice that overexpress nSREBP-1c in adipose tissue under the control of the adipocyte-specific aP2 enhancer/promoter. A syndrome with the following features was observed: (1) Disordered differentiation of adipose tissue. White fat failed to differentiate fully, and the size of white fat depots was markedly decreased. Brown fat was hypertrophic and contained fat-laden cells resembling immature white fat. Levels of mRNA encoding adipocyte differentiation markers (C/EBP alpha, PPAR gamma, adipsin, leptin, UCP1) were reduced, but levels of Pref-1 and TNF alpha were increased. (2) Marked insulin resistance with 60-fold elevation in plasma insulin. (3) Diabetes mellitus with elevated blood glucose (>300 mg/dl) that failed to decline when insulin was injected. (4) Fatty Liver from birth and elevated plasma triglyceride levels later in life. These mice exhibit many of the features of congenital generalized lipodystrophy (CGL), an autosomal recessive disorder in humans.