Investigation of role of hypothalamic glucokinase in the control of food intake

食物的摄入部分是由大脑调节的，特别是大脑中被称为下丘脑的部分。长期以来，人们一直认为葡萄糖在食物摄入的调节中具有特定的作用，称为食物摄入的葡萄糖抑制调节。然而，到目前为止，这种情况发生的机制尚不清楚。我们最近发现，一种存在于下丘脑中的称为葡萄糖激酶的酶可能是这种机制的重要组成部分。我们发现，禁食大鼠下丘脑一个叫做弓状核的特定部位的葡萄糖激酶活性水平增加。当我们使用一种病毒（rAAV）在弓状核中过表达葡萄糖激酶来模拟葡萄糖激酶活性的增加时，我们发现它导致了食物摄入的减少。这种效应似乎是由于饮食中的葡萄糖，因为当大鼠获得葡萄糖溶液时;那些在弓形体中葡萄糖激酶活性增加的大鼠比葡萄糖激酶水平正常的大鼠消耗更少的葡萄糖。这种效应似乎是特定的葡萄糖，因为当大鼠喂食密切相关的糖果糖时，两组之间的摄入量没有差异。然后，我们研究了葡萄糖激酶的这种变化是否可以解释食物摄入的葡萄糖抑制调节。为了研究这一点，给予大鼠固定量的葡萄糖溶液，然后测量食物摄入量。我们发现，与葡萄糖激酶水平正常的对照组大鼠相比，在弓状核葡萄糖激酶活性增加的大鼠中，食物摄入量减少。这表明下丘脑中的葡萄糖激酶在响应于葡萄糖摄入的食物摄入的调节中起重要作用。我们现在计划研究葡萄糖激酶是否在长期食物摄入和体重增加的调节中发挥作用。我们将使用rAAV来过度表达和减少弓状核中葡萄糖激酶的表达，并检查对长期食物摄入和体重增加的影响。将检查在饮食中补充葡萄糖对摄食量和体重增加的影响。我们还将研究弓状核中葡萄糖激酶水平的升高或降低是否会改变对高脂饮食的反应。此外，我们将研究是否补充高脂肪饮食与葡萄糖改变食物摄入量和体重增加。我们将研究葡萄糖激酶和其他已知的调节剂之间的相互作用的能量稳态下丘脑。总之，这项工作将使我们能够调查的生理作用，葡萄糖激酶在弓状核中的调节食物摄入量，并确定它是否是一个可能的机制，其中葡萄糖抑制调节食物摄入量发生。这将确定下丘脑葡萄糖激酶是否可能成为制药行业感兴趣的目标。

Food intake is regulated in part by the brain and in particular part of the brain called the hypothalamus. It has for a long time been thought that glucose has a specific role in the regulation of food intake, known as the glucostatic regulation of food intake. However until now the mechanism by which this occurs has been unclear. We have recently found that an enzyme called glucokinase which is present in the hypothalamus may be an important part of this mechanism. We have found that in fasting rats levels of glucokinase activity in a specific part of the hypothalamus called the arcuate nucleus are increased. When we mimicked this increase in glucokinase activity using a type of virus (rAAV) to over-express glucokinase in the arcuate nucleus we found it caused a decrease in food intake. This effect seems to be due to glucose in the diet since when rats were given access to a glucose solution; those in which we had increased glucokinase activity in the arcuate consumed less glucose than those with normal levels of glucokinase. This effect appears to be specific for glucose since when rats were fed a closely related sugar fructose there was no difference in intake between the two groups. We then investigated whether this change in glucokinase could explain the glucostatic regulation of food intake. To investigate this, rats were given a fixed amount of glucose solution and after which there food intake was measured. We found that in rats in which we had increased glucokinase activity in their arcuate nucleus food intake was reduced compared to control rats with normal glucokinase levels. This suggests that glucokinase in the hypothalamus plays an important role in the regulation of food intake in response to intake of glucose. We now plan to investigate whether glucokinase plays a role in the regulation of long-term food intake and weight gain. We will use rAAV to both over-express and decrease expression of glucokinase in the arcuate nucleus and examine the effect on long-term food intake and weight gain. The effect of supplementing the diet with glucose on food intake and body weight gain will be examined. We will also examine whether increased or decreased levels of glucokinase in the arcuate nucleus alter the response to a high fat diet. In addition we will examine whether supplementation of a high fat diet with glucose alters food intake and weight gain. We will examine the interaction between glucokinase and other known modulators of energy homeostasis in the hypothalamus. Together this work will allow us to investigate the physiological role of glucokinase in the arcuate nucleus in the regulation of food intake and determine if it is a possible mechanism by which the glucostatic regulation of food intake occurs. This will establish whether hypothalamic glucokinase may be a target of interest to the pharmaceutical industry.