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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470225/
• 关键词: leptin; lipoatrophic diabetes; adrenoceptor; microarray; fatty acid; respiration; マイクロアレイ法; トランスジェニックマウス; 脂肪酸合成; 脂肪酸酸化; 肝臓; 糖代謝; 脂質代謝; A-ZIPTgマウス; 塩酸ブナゾジン

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.

我们已经证明了抗LeSulin抗糖尿病的过表达和肝脏中的肝脂肪变性。 。使用cDNA微阵列分析在糖尿病效应中，Microarray分析显示，与LETG中的肝脏中有关糖酵解，呼吸链和胰岛素信号转导的上调。瘦素的转基因过表达恢复了大量基因的表达，在A-Zittg/A-ZITTG小鼠中改变了瘦素概念。脂肪营养性糖尿病中的肝基因表达从葡萄糖利用和脂肪酸合成到脂肪酸和增加的呼吸性的能量代谢中的变化。

项目成果

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N.Matsuoka 等人：“过度表达瘦素的转基因瘦小鼠中富含甘油三酯的脂蛋白减少”Am。

M.Shintani et al.: "Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway"Diabetes. 50. 227-232 (2001)

M.Shintani 等人：“Ghrelin 是一种内源性生长激素促分泌素，是一种新型的食欲肽，通过激活下丘脑神经肽 Y/Y1 受体途径来拮抗瘦素作用”。

K.Shimizu et al.: "Plasma leptin levels and cardiac sympathetic function in patients with obstructive sleep apnoea-hypopnoea syndrome"Thorax. 57. 429-434 (2002)

K.Shimizu 等人：“阻塞性睡眠呼吸暂停低通气综合征患者的血浆瘦素水平和心脏交感功能”胸部。

H.Chusho et al.: "Dwarfism and early death in mice lacking C-type natriuretic Peptide"Proc. Natl. Acad. Sci. USA. 98. 4016-4021 (2001)

H.Chusho 等人：“缺乏 C 型利尿钠肽的小鼠的侏儒症和早期死亡”Proc。

T.Nakagawa et al.: "Antiobesity and antidiabetic effects of brain-derived neurotrophic factor in rodent models of leptin resistance"Int. J. Obes.. 27. 557-565 (2003)

T.Nakakawa 等人：“脑源性神经营养因子在瘦素抵抗啮齿动物模型中的抗肥胖和抗糖尿病作用”Int。