Improvement in glycemia after glucose or insulin overload in leptin-infused rats is associated with insulin-related acti
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Improvement in glycemia after glucose or insulin overload in leptin-infused rats is associated with insulin-related activation of hepatic glucose metabolism Emma Burgos-Ramos1,5, Sandra Canelles1,2, Laura M. Frago1,2,3, Julie A. Chowen1,2, Eduardo Arilla-Ferreiro4, Jesús Argente1,2,3 and Vicente Barrios1,2*
Abstract Background: Insulin regulates glucose homeostasis through direct effects on the liver, among other organs, with leptin modulating insulin’s hepatic actions. Since central leptin may modify insulin signaling in the liver, we hypothesized that leptin infusion activates hepatic glycogen synthesis following peripheral administration of a bolus of glucose or insulin, thus regulating glycemia. Findings: Oral glucose and intraperitoneal insulin tolerance tests were performed in control, intracerebroventricular leptin-treated and pair-fed rats during 14 days. An improvement in glycemia and an increase in hepatic free glucose and glycogen concentrations after glucose or insulin overload were observed in leptin-treated rats. In order to analyze whether the liver was involved in these changes, we studied activation of insulin signaling by Western blotting and multiplex bead immunoassay after leptin infusion. Our studies revealed an increase in phosphorylation of insulin receptor substrate-1 and Akt in leptin-treated rats. Examination of parameters related to glucose uptake and metabolism in the liver revealed an augment in glucose transporter 2 and a decrease in phosphoenolpyruvate carboxylase protein levels in this group. Conclusions: These results indicate that central leptin increases hepatic insulin signaling, associated with increased glycogen concentrations after glucose or insulin overload, leading to an improvement in glycemia. Keywords: Glycemia, Glycogen synthesis, Insulin signaling, Leptin, Liver, Tolerance test
Findings Introduction
Leptin modulates hepatic insulin action [1] and is a key regulator of carbohydrate homeostasis. Under physiological conditions, insulin modulates glucose fluxes by suppressing the expression of gluconeogenic genes and stimulating those associated with glucose uptake. Leptin is involved in these actions through stimulation of phosphatidylinositol-3 kinase [2]. * Correspondence: [email protected] 1 Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Avda. Menéndez Pelayo, 65, E-28009 Madrid, Spain 2 Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid E-28009, Spain Full list of author information is available at the end of the article
Intravenous [3] and brain infusions of leptin [4] alter hepatic glucose fluxes, improving glucose homeostasis. These effects on insulin’s actions in peripheral organs have been examined in models of obesity and diabetes [5], however; there is little information regarding the effects of an increase in central leptin bioavailability on hepatic insulin
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