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

食物摄入量在一定程度上受到大脑的调节，特别是大脑的下丘脑部分。长期以来，人们一直认为葡萄糖在食物摄入量的调节中具有特定的作用，被称为食物摄入量的血糖调节。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，下丘脑中存在的一种名为葡萄糖激酶的酶可能是这一机制的重要组成部分。我们发现，在禁食的大鼠中，下丘脑中称为弓状核的特定部分的葡萄糖激酶活性水平增加。当我们用一种病毒(RAAV)在弓状核过度表达葡萄糖激酶时，我们模拟了葡萄糖激酶活性的增加，我们发现它导致了食物摄入量的减少。这种影响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，我们增加了弓状体内葡萄糖激酶活性的老鼠比那些葡萄糖激酶水平正常的老鼠消耗了更少的葡萄糖。这种影响似乎是葡萄糖特有的，因为当老鼠喂食一种密切相关的果糖时，两组之间的摄入量没有差异。然后，我们调查了葡萄糖激酶的这种变化是否可以解释食物摄入量的血糖调节。为了研究这一点，给大鼠提供了固定数量的葡萄糖溶液，然后测量了它们的食物摄入量。我们发现，在弓状核葡萄糖激酶活性增加的大鼠中，与葡萄糖激酶水平正常的对照组相比，食物摄入量减少。这表明下丘脑中的葡萄糖激酶在调节摄食对葡萄糖摄取的反应中起着重要作用。我们现在计划调查葡萄糖激酶是否在调节长期食物摄入量和体重增加方面发挥作用。我们将使用rAAV在弓状核中过度表达和降低葡糖激酶的表达，并检测其对长期食物摄入量和体重增加的影响。研究补充葡萄糖对食物摄入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增加或减少是否会改变对高脂肪饮食的反应。此外，我们还将研究补充含葡萄糖的高脂肪饮食是否会改变食物摄入量和体重增加。我们将研究葡糖激酶和下丘脑中其他已知的能量平衡调节器之间的相互作用。总之，这项工作将使我们能够研究弓状核中葡萄糖激酶在调节食物摄入量中的生理作用，并确定这是否是一种可能的机制，通过它来调节食物摄入量。这将确定下丘脑葡萄糖激酶是否可能是制药业感兴趣的目标。

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.