Control of metabolic diseases by means of brain function in mammals

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。我们培育了表达人类生长激素（hGH）、hGH受体（hGHR）和瘦素的转基因大鼠。由于缺乏内源性生长激素脉冲，转基因大鼠表现出过度肥胖。另一方面，在同时表达hGH和hGHR的双基因大鼠中，脂肪组织质量和血清瘦素水平降低。这些动物是分析GH搏动和脂质代谢的有用模型。本研究还研究了将GABA合成酶谷氨酸脱羧酶（glutamic acid decarboxylase， GAD）的反义寡核苷酸（ODNs）（由GAD65和GAD67两种同工酶组成）注射到雄性大鼠VMH后对摄食量、体重和运动活性的影响。结果表明，GAD65主要参与增加VMH大鼠的食物摄取量和抑制运动活动。本研究还表明，中心注射反义寡脱氧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是通过调节下丘脑的GH搏动和GAD 65基因表达来控制的。

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.