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

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(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.