Essential role of STAT3 in body weight and glucose homeostasis
Essential role of STAT3 in body weight and glucose homeostasis
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DOI：
10.1128/mcb.24.1.258-269.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
Li, C
中科院分区：
文献类型：
--
作者：
Cui, YX;Huang, L;Li, C
STAT3是一种普遍存在的转录因子，在早期胚胎发育过程中不可或缺。为了研究STAT3在出生后的功能，我们产生了条件性STAT3缺陷小鼠。为此，将STAT3(lox/lox)小鼠与在大鼠胰岛素II基因启动子控制下表达Cre的小鼠(RIP-Cre小鼠)杂交。免疫组织化学和Western印迹分析表明，STAT3在朗格汉斯胰岛的β细胞中被删除。基因组DNA聚合酶链式反应显示，STAT3基因缺失也发生在下丘脑。将RIP-Cre/STAT3(lox/lox)小鼠与rosa26Cre报告菌株杂交，并对LacZ活性进行染色，进一步证实了下丘脑Cre的表达。免疫组织化学双重染色证实瘦素受体(OB-Rb亚型)阳性神经元中存在STAT3的缺失。RIP-CRE/STAT3(lox/lox)小鼠在断奶时表现为轻度高血糖和高胰岛素血症，在断奶后立即出现高血压症，并表现出糖耐量受损。RIP-CRE/STAT3(lox/lox)小鼠的体重、体脂以及瘦素的mRNA和蛋白质水平都显著增加。脑室注射重组瘦素不能使RIP-Cre/STAT3(lox/lox)小鼠的体脂完全消失。将野生型胰岛移植到RIP-Cre/STAT3(lox/lox)小鼠体内也未能减少肥胖或纠正这些小鼠的其他异常。因此，这些数据表明，RIP-CRE作用引起的下丘脑STAT3的丢失可能会干扰正常体重、动态平衡和葡萄糖代谢。
STAT3 is a ubiquitous transcription factor that is indispensable during early embryogenesis. To study the functions of STAT3 postnatally, we generated conditional STAT3-deficient mice. To that end, STAT3(lox/lox) mice were crossed with mice expressing Cre under the control of rat insulin II gene promoter (RIP-Cre mice). Immunohistochemical and Western blot analyses showed that STAT3 is deleted from beta cells in the islets of Langerhans. Genomic DNA PCR revealed that STAT3 deletion also occurred in the hypothalamus. Hypothalamic Cre expression was further confirmed by crossing RIP-Cre/STAT3(lox/lox) mice with the ROSA26 Cre reporter strain and staining for lacZ activity. Double immunohistochemical staining confirmed that deletion of STAT3 occurred in leptin receptor (OB-Rb isoform)-positive neurons. RIP-Cre/STAT3(lox/lox) mice are mildly hyperglycemic and hyperinsulinemic at the time of weaning, become hyperphagic immediately after weaning, and exhibit impaired glucose tolerance. Body weight, body fat, and mRNA and protein levels of leptin are all significantly increased in RIP-Cre/STAT3(lox/lox) mice. Administration of recombinant leptin by intracerebroventricular infusion failed to cause complete loss of body fat in RIP-Cre/STAT3(lox/lox) mice. Transplantation of wild-type islets into RIP-Cre/STAT3(lox/lox) mice also failed to decrease adiposity or to correct other abnormalities in these mice. These data thus suggest that loss of STAT3 in the hypothalamus caused by RIP-Cre action likely interferes with normal body weight homeostasis and glucose metabolism.