Control of metabolic diseases by means of brain function in mammals

通过哺乳动物的脑功能控制代谢疾病

• 批准号: 08306016
• 负责人: TAKAHASHI Michio
• 金额: $ 13.95万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08306016/
• 关键词: Hypothalamus; Feeding behavior; Metabolism; Diabetes mellitus; Obesity; Growth hormone; Leptin; Transgenic rats

The purpose of this study was to elucidate hypothalamic neuronal mechanisms controlling metabolism and feeding behavior and to regulate obesity, diabetes and abnormal feeding. We produced transgenic rats expressing human growth hormone (hGH), hGH receptor (hGHR) and leptin. The hGH transgenic rats showed excessive obesity due to the lack of endogenous GH pulses. On the other hand, in the bigenic rats expressing both hGH and hGHR, adipose tissue mass and serum leptin levels were decreased. These animals are useful models to analyze GH pulsatility and lipid metabolism. In the present study, we also examined the effect of injection of anti sense oligodeoxynucleotides (ODNs) of GABA synthetic enzyme, glutamic acid decarboxylase (GAD) that consists of two isozymes, GAD65 and GAD67, into the VMH of the male rat on food intake, body weight and locomotor activity. The results suggested that GAD65 was mainly involved in enhancing food intake and suppressing locomotor activity in rat VMH.This study also indicates that central injection of antisense oligodeoxynucleotides is useful means to regulate animal metabolism. From these studies, symptoms such as obesity, diabetes and abnormal feeding may be controlled by regulating GH pulsatility and gene expression of GAD 65 in they hypothalamus.

本研究的目的是阐明下丘脑神经元控制代谢和摄食行为的机制，并调节肥胖、糖尿病和异常摄食。我们获得了表达人生长激素(HGH)、hGH受体(HGHR)和瘦素的转基因大鼠。HGH转基因大鼠由于缺乏内源性GH脉冲而表现出过度肥胖。另一方面，在同时表达hGH和hGHR的大鼠中，脂肪组织质量和血清瘦素水平下降。这些动物是分析生长激素搏动性和脂肪代谢的有用模型。在本研究中，我们还观察了向雄性大鼠VMH注射由GAD65和GAD67两种同工酶组成的GABA合成酶的反义寡核苷酸(ODN)--谷氨酸脱羧酶(GAD)对摄食量、体重和运动能力的影响。结果提示，GAD65主要参与增加大鼠VMH的摄食量和抑制运动活动。提示中枢注射反义寡核苷酸是调节动物代谢的有效手段。从这些研究来看，肥胖、糖尿病和进食异常等症状可能通过调节GH的脉动性和下丘脑GAD 65的基因表达来控制。

项目成果

Bannai M: "Effect of injection of antisense oligonucleotides of GAD isozymes into rat VMH on food intake and locomotor activity" Brain Research(印刷中). (1998)

Bannai M：“将 GAD 同工酶反义寡核苷酸注射到大鼠 VMH 对食物摄入和运动活动的影响”《大脑研究》（出版中）（1998 年）。

Bannai M,他: "Water-absorbent polymer as a carrier for a discrete deposit of antisense oligodeoxynucleotides in the central nervous system" Brain Research Protocols. 3. 83-87 (1998)

Bannai M 等人：“吸水性聚合物作为中枢神经系统中反义寡脱氧核苷酸离散沉积的载体”《大脑研究方案》3. 83-87 (1998)。

Chang KT,et al.: "Possible mechanisms for the testis-mediated gene transfer as a new method for producing transgenic animals" Journal of Reproduction and Development. 45. 37-42 (1999)

Chang KT 等人：“睾丸介导的基因转移作为生产转基因动物的新方法的可能机制”《生殖与发育杂志》。

Ikeda A,et al.: "Obesity and insulin resistance in human growth hormone (hGH) transgenic rats" Endocrinology. 139. 3057-3063 (1998)

Ikeda A 等人：“人生长激素 (hGH) 转基因大鼠的肥胖和胰岛素抵抗”内分泌学。

Bannai M,et al.: "Effect of injection of antisense oligonucleotides GAD isozymes into rat VMH on food intake and locomotor activity" Brain Research. 784. 305-315 (1998)

Bannai M 等人：“将反义寡核苷酸 GAD 同工酶注射到大鼠 VMH 中对食物摄入和运动活动的影响”大脑研究。