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Submitted on November 17, 2005
Accepted on February 10, 2006
From Neuroendocrinologie Moléculaire de la Prise Alimentaire, NOPA, INRA, Université Paris XI, IBAIC Bat. 447, Orsay 91405, France. The Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, PO Box 12, Rehovot 76100, Israel. Institut National de Recherche Médicale, Equipe Avenir, Paris F-75004 France; Université Pierre and Marie Curie, Paris, F-75006 France
* To whom correspondence should be addressed. E-mail: mohammed.taouis{at}ibaic.u-psud.fr.
The insulin-sensitive glucose transporter Glut4 is expressed in brain areas that regulate energy homeostasis and body adiposity. In contrast with peripheral tissues however, the impact of insulin on Glut4 plasma membrane translocation in neurons is not known. In this study, we examined the role of two anorexic hormones (leptin and insulin) on Glut4 translocation in a human neuronal cell line that express endogenous insulin and leptin receptors. We show that insulin and leptin both induce Glut4 translocation to the plasma membrane of neuronal cells and activate glucose uptake. Wortmannin, a specific inhibitor of PI 3-kinase, totally abolished insulin- and leptin- dependent Glut4 translocation and stimulation of glucose uptake. Thus, Glut4 translocation is a PI 3-kinase-dependent mechanism in neuronal cells. Next, we investigated the impact of chronic insulin and leptin treatments on Glut4 expression and translocation. Chronic exposure of neuronal cells to insulin or leptin down-regulates Glut4 proteins and mRNA levels, and abolishes the acute stimulation of glucose uptake in response to acute insulin or leptin. In addition, chronic treatment with either insulin or leptin impaired Glut4 translocation. A cross-desensitization between insulin and leptin was apparent, where exposure to insulin affects leptin-dependent Glut4 translocation and vice versa. This cross-desensitization could be attributed to the increase in SOCS-3 expression, which was demonstrated in response to each hormone. These results provide evidence to suggest that Glut4 translocation to neuronal plasma membrane is regulated by both insulin and leptin signaling pathways. These pathways might contribute to an in vivo glucoregulatory reflex involving a neuronal network and to the anorectic effect of insulin and leptin.
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