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Molecular mechanism of leptin-induced increase in glucose and lipid metabolism

瘦素诱导糖脂代谢增加的分子机制

基本信息

批准号：
13470225
负责人：
OGAWA Yoshihiro
金额：
$ 9.09万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

We have demonstrated that transgenic overexpression of leptin can rescue the insulin-resistant diabetes and hepatic steatosis in a mouse model of lipoatrophic diabetes (A-ZIPTg mice), suggesting the potential usefulness of leptin as an antidiabetic agent. However, the molecular mechanisms underlying the leptin-induced increase in glucose and lipid metabolism is not clear. In this study, we examined the effect of sympathetic blockade on the leptin-induced increase in glucose metabolism in LepTg/A-ZIPTg mice obtained through genetic cross between transgenic skinny mice overexpressing letpin (LepTg) and A-ZIPTg mice. We also characterized the profile of hepatic gene expression in LepTg/A-ZIPTg mice using cDNA microarray analysis. Intraperitoenal injection of α-adrenoceptor blocker (bunazasin) did not affect the improved glucose metabolism in LepTg/A-ZIPTg mice. However, β-adrenoceptor blocker (propranolol) did aggravate the glucose metabolism in the animals. Those observations suggest the involvement of β-adrenoceptor activation in the lepitn's antidiabetic effect.Microarray analysis showed the upregulation in mRNAs encoding genes involved in glycolysis, respiratory chain, and insulin signal transduction in the liver from LepTg. By contrast, the expression of a wide variety of genes involved in fatty acid synthesis and oxidation programs was increased in A-ZIPTg mice. However, transgenic overexpression of leptin restored the expression of a large subset of genes, which are altered in A-ZIPTg mice, in LepTg/A-ZIPTg mice. Exogenous administration of leptin that elevates plasma leptin concentrations to those of LepTg/A-ZIPTg mice also resulted in the normalization of hepatic expressions of these genes in A-ZIPTg mice. These observations suggest that leptin alters hepatic gene expression in lipoatrophic diabetes, which leads to a change in energy metabolism from glucose utilization and fatty acid synthesis to fatty acid oxidation and increased respiration.

我们已经证明，转基因过表达瘦素可以挽救胰岛素抵抗型糖尿病和脂肪肝的脂肪萎缩性糖尿病小鼠模型（A-ZIPTg小鼠），这表明瘦素作为一种抗糖尿病剂的潜在用途。然而，瘦素诱导的糖脂代谢增加的分子机制尚不清楚。在这项研究中，我们研究了交感神经阻滞对瘦素诱导的LepTg/A-ZIPTg小鼠葡萄糖代谢增加的影响，该小鼠是通过过表达瘦素的转基因瘦小鼠（LepTg）和A-ZIPTg小鼠之间的遗传杂交获得的。我们还使用cDNA微阵列分析LepTg/A-ZIPTg小鼠的肝脏基因表达谱。腹腔注射α-肾上腺素能受体阻断剂（布那他辛）对LepTg/A-ZIPTg小鼠糖代谢的改善无影响。而β-肾上腺素能受体阻断剂（心得安）可加重动物的糖代谢。这些观察结果表明，β-肾上腺素受体的激活参与lepitn的抗糖尿病作用。芯片分析显示，上调基因编码基因参与糖酵解，呼吸链，胰岛素信号转导在肝脏中从LepTg。相比之下，在A-ZIPTg小鼠中，参与脂肪酸合成和氧化程序的各种基因的表达增加。然而，在LepTg/A-ZIPTg小鼠中，瘦素的转基因过表达恢复了在A-ZIPTg小鼠中改变的基因的大子集的表达。外源性给予瘦素，使血浆瘦素浓度升高至LepTg/A-ZIPTg小鼠的水平，也导致A-ZIPTg小鼠中这些基因的肝脏表达正常化。这些观察结果表明，瘦素改变脂肪萎缩性糖尿病的肝脏基因表达，导致能量代谢从葡萄糖利用和脂肪酸合成到脂肪酸氧化和呼吸增加的变化。