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Resistin Regulates Pituitary Somatotrope Cell Function through the Activation of Multiple Signaling Pathways

Department of Cell Biology, Physiology, and Immunology (F.R.-P., R.V.-M., A.J.M.-F., M.R.P., M.D.G., F.G.-N., J.P.C., M.M.M.), University of Córdoba, E-14014 Córdoba, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (F.R.-P., R.V.-M., A.J.M.-F., M.R.P., M.D.G., F.G.-N., C.D., J.P.C., M.M.M.), E-14004 Córdoba, Spain; Institut National de la Santé et de la Recherche Médicale Unité 413 (H.V.), Laboratory of Cellular and Molecular Neuroendocrinology, 76821 Mont-Saint-Aignan, France; and Department of Physiology (C.D.), University of Santiago de Compostela, E-15705 Santiago de Compostela, Spain

Address all correspondence and requests for reprints to: María M. Malagón, Department of Cell Biology, Physiology, and Immunology, Edificio Severo Ochoa, Planta 3, Campus de Rabanales, University of Córdoba, E-14014 Córdoba, Spain. E-mail: bc1mapom{at}uco.es.

The adipokine resistin is an insulin-antagonizing factor that also plays a regulatory role in inflammation, immunity, food intake, and gonadal function. Although adipose tissue is the primary source of resistin, it is also expressed in other tissues and organs, including the pituitary. However, there is no information on whether resistin, as described previously for other adipokines such as leptin and adiponectin, could regulate this gland. Likewise, the molecular basis of resistin actions remains largely unexplored. Here we show that administration of resistin to dispersed rat anterior pituitary cells increased GH release in both the short (4 h) and long (24 h) term, decreased mRNA levels of the receptor of the somatotrope regulator ghrelin, and increased free cytosolic Ca²⁺ concentration in single somatotropes. By means of a pharmacological approach, we found that the stimulatory action of resistin occurs through a Gs protein-dependent mechanism and that the adenylate cyclase/cAMP/protein kinase A pathway, the phosphatidylinositol 3-kinase/Akt pathway, protein kinase C, and extracellular Ca²⁺ entry through L-type voltage-sensitive Ca²⁺ channels are essential players in mediating the effects of resistin on somatotropes. Taken together, our results demonstrate for the first time a regulatory role for resistin on somatotrope function and provide novel insights on the intracellular mechanisms activated by this protein.