New Animal Models Of Leaness And Obesity by Genetic Engineering and its Application to Therapy

(目的)能量代谢调节失调会导致糖尿病和肥胖。糖尿病和肥胖症是心血管疾病的主要危险因素，阐明肥胖症的病理生理机制和药物的开发具有重要意义。在本研究中，为了阐明能量代谢的调节，我们建立了一种能量代谢分子中的转基因小鼠。我们建立了在肝脏过度表达瘦素的转基因小鼠，并检测了瘦素的慢性作用。(方法)通过显微注射BDF1小鼠肝脏和卵细胞中特异的血清淀粉样组分P启动子控制的瘦素基因，建立了转基因小鼠。我们检测了食物摄入量、体重和体温。(结果)瘦素转基因小鼠(TG小鼠)的循环瘦素水平约为100 ng/ml，约为对照小鼠的10倍。转基因小鼠的体重约为对照组的70%，脂肪较少，因为白色和棕色的脂肪组织大多缺失。IPGTT组和IPIIT组的胰岛素敏感性增加，体温升高1.5-2。(讨论)在本研究中，我们成功地创造了瘦素转基因小鼠，其中循环中的瘦素水平是对照小鼠的10倍。转基因小鼠的体重是对照组的70%，无脂肪。体温升高提示瘦素参与能量消耗。TG小鼠被认为是研究瘦素慢性作用的良好模型，是一种新的瘦素动物模型。对瘦素后能量代谢调控信号的研究将有助于了解能量代谢分子的整体特征。

(Purpose) Disorders in regulation of energy metabolism lead to diabetes and obesity. Since diabetes and obesity are main risk factors of caridovascular diseases, elucidation of pathophysilogy of obesity and development of drugs are important. In the present study, in order to elucidate regulation of energy metabolism, we developed transgenic mice in a molecule of energy metabolism. We created transgenic mice overexpressing leptin in the liver, and examined chronic action of leptin.(Methods) We created transgenic mice by microinjection of vector in which leptin cDNA is under the control of serum amyloid component P promoter, which is specific in the liver to eggs of BDF1 mice. We examined food intake, body weight, and body temperature.(Results) Circulating leptin levels in the leptin-transgenic mice (Tg mice) are approximately 100ng/ml, about 10-fold of those of control mice. The Tg mice are approximately 70 % of the control mice in weight, and fat less as white and brown adipose tissues are mostly absent. Increase of insulin sensitivity were observed in IPGTT and IPIIT.Furthermore, increase of body temperature by 1.5-2 。C and significant elevation of systemic blood pressure (119.2 * 2.3 vs. 102.6 * 2.6 mmHg, P < 0.001) are noted.(Discussion) In the present study, we succeeded in creating leptin transgenic mice, in which circulating leptin levels are 10-fold of the control mice. The Tg mice are 70 % in body weight as compared with the control mice, are fatless. The increase of body temperature indictates the involvement of leptin in energy expenditure. The Tg mice are considered to be a good model for the study of chronic action of leptin, and are a new animal model of leaness. The study of post-leptin signal of regulation in energy metabolism will lead to the understanding of overall feature of molecules in energy metabolism.