Abstract EN:

We are investigating the mechanisms by which cells sense and adapt their functions to their nutritional environment, focusing on glucose detection. Glucose is not only a substrate for most cells but it also generates a signal to the nucleus that regulates gene transcription. In culture cells, we can block the stimulation of glucose sensitive gene transcription by inhibiting glucose metabolism or by expressing a GLUT2 loop domain that leaves unaffected glucose metabolism. Thus the detection of extracellular glucose triggered by GLUT2 can be studied independently of intracellular glucose metabolism. To evaluate in vivo, the importance of this detection pathway, we produced transgenic mice that expressed ubiquitously the GLUT2 loop domain. Transgenic mice displayed increased daily food intake and perturbed hypothalamic expression of orexigenic and anorexigenic peptides. Interestingly, meal consumptions were neither reduced after a glucose injection nor increased after 2-deoxyglucose injection, suggesting a poor detection of glucose abundance or glucopenia. We recorded by indirect calorimetry that mice favoured lipid over glucose oxidation in accordance with their low fat mass. During an oral glucose challenge, we underlined a significantly reduced plasma insulin response. Together pancreatic and hypothalamic failures to detect glucose could contribute to the growth retardation of transgenic mice. Nevertheless, insulin tolerance tests were unchanged suggesting that peripheral tissues, that are not expressing GLUT2, were unaffected in these mice. Taken together, these data suggest that the detection of extracellular sugar mediated by GLUT2 in pancreas and brain, without affecting their basal functions, controls multiple aspects of food intake, satiety and glucose homeostasis. The sugar detector GLUT2 might constitute a new therapeutic target for the benefit of patients suffering from food intake disorders.