[Contribution of metabolic sensors on feeding behaviour and the control of body weight].

Metabolic sensors play an important role in the control of food intake, utilization of nutrients and demonstration of feeding behaviour. In this work we describe the study done in our laboratory on glucokinase (GK) as brain glucose sensor, the AMP kinase (AMPK) as detector of the fall of intracellular energy charge and as the S6K in the signaling pathway of mTOR with opposite effects to AMPK. Glucose sensors are molecular designs that detect with accuracy glucose concentrations, facilitating therefore the homeostasis of this hexose. We consider GK as a component of a glucose sensor system that might modulates the feeding behaviour and indirectly the control of body weight. Our findings indicate that GK and GLUT-2 mRNAs and proteins are coexpressed mainly in areas of the hypothalamus implied in the control of food intake. We have also found a high glucose phosphorylating activity with kinetic properties similar to that reported in the liver, with a high apparent Km for glucose that displays no product inhibition by glucose-6-phosphate. GK may be also regulated by the presence of glucokinase regulatory protein (GKRP), which has been identified in the same brain areas than GK. The coexpression of these molecules might play a role as glucose sensors in which GLUT-2 has a permissive role and the interactions of GK with GKRP made possible a real sensor activity. Furthermore, the effects of anorexigenic peptides in this system should facilitate the transduction of signals required to produce a state of satiety. Thus, GLP-1 reduced significantly the glucose metabolism in areas of the hypothalamus and brainstem related with food intake, which open new ways to the study of pathophysiologicals aspects of feeding behaviour. Besides we have studied the functions of AMPK and mTOR pathway in the hypothalamic areas ventromedial (VMH) and lateral (LH) under situations with alterations of the nutritional status and energy balance. Our results revealed that the activation of AMPK and S6K in VMH y LH occur in response to the changes of glucose concentrations or in the changes in the nutritional state, as well as GLP-1/exendin-4 act by counteracting the activation/inactivation of these kinases, which support a modulating role of these peptides on the kinases. On the other hand, GLP-1/exendin-4 might contribute to the normalization of the altered values of these kinases in pathophysiological states such as obesity.