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Diabetes 53:347-353, 2004
© 2004 by the American Diabetes Association, Inc.

Leptin Impairs Insulin Signaling in Rat Adipocytes

Coralia Pérez1, Carmen Fernández-Galaz2, Teresa Fernández-Agulló2, Carmen Arribas3, Antonio Andrés4, Manuel Ros2, and José M. Carrascosa1

1 Centre of Molecular Biology "Severo Ochoa," Autonomous University, Madrid, Spain
2 Health Sciences Faculty, University Rey Juan Carlos, Alcorcón, Madrid, Spain
3 Environment Sciences Faculty, Regional Centre for Biomedical Research, University of Castilla La Mancha, Toledo, Spain
4 Biochemistry Section, Faculty of Chemistry, Regional Centre for Biomedical Research, University of Castilla La Mancha, Ciudad Real, Spain

Leptin modulates glucose homeostasis by acting as an insulin-sensitizing factor in most insulin target tissues. Nevertheless, insulin-dependent glucose uptake in white adipose tissue decreases after in vivo treatment with leptin. Moreover, elevated leptin concentrations inhibit insulin metabolic effects in adipocytes. Here we studied both, direct and centrally mediated effects of leptin on insulin signaling in rat adipocytes. Adipocyte incubation with low leptin concentrations did not modify the insulin stimulation of mitogen-activated protein kinase (MAPK). However, at elevated concentrations, leptin impaired insulin-stimulated MAPK activity, glycogen synthase kinase (GSK)3ß phosphorylation, and insulin receptor tyrosine phosphorylation without altering vanadate stimulation. An increase of suppressor of cytokine signaling-3 protein was also observed. Central administration of leptin decreased insulin effects on adipocyte MAPK and GSK3ß phosphorylation. In insulin-resistant aged rats with hyperleptinemia and central leptin resistance, insulin poorly stimulated MAPK and central leptin infusion did not further deteriorate adipocyte insulin responsiveness. Food restriction increased MAPK stimulation by insulin and restored the ability of centrally infused leptin to attenuate adipocyte insulin signaling in aged rats. We conclude that leptin can modulate, in an inhibitory manner, adipocyte insulin signaling by two different ways: as an autocrine signal and, indirectly, through neuroendocrine pathways. These mechanisms may be of relevance in situations of hyperleptinemia, such as aging and/or obesity.

Address correspondence and reprint requests to Prof. José M. Carrascosa, Centro de Biología Molecular "Severo Ochoa," Facultad de Ciencias, Universidad Autónoma, Campus de Cantoblanco, 28049 Madrid, Spain. E-mail: jmcarrascosa{at}cbm.uam.es


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Copyright © 2004 by the American Diabetes Association.