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

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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.