Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Author Carvalheira, José Barreto Campello Google Scholar
Ribeiro, Eliane Beraldi Autor UNIFESP Google Scholar
Araujo, Eliana Pereira de Google Scholar
Guimaraes, Regina Barros Google Scholar
Telles, Monica Marques Autor UNIFESP Google Scholar
Torsoni, Marcio Alberto Google Scholar
Gontijo, Jose Antonio Rocha Google Scholar
Velloso, Licio Augusto Google Scholar
Saad, Maria Jose Abdalla Google Scholar
Institution Universidade Estadual de Campinas (UNICAMP)
Universidade Federal de São Paulo (UNIFESP)
Abstract Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states.Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats.Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. the relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. in contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats.Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance.
Keywords obesity
insulin resistance
hypothalamus
anorexia
signal transduction
phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism
mitogen-activated protein kinase
Language English
Date 2003-12-01
Published in Diabetologia. New York: Springer-verlag, v. 46, n. 12, p. 1629-1640, 2003.
ISSN 0012-186X (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 1629-1640
Origin http://dx.doi.org/10.1007/s00125-003-1246-x
Access rights Closed access
Type Article
Web of Science ID WOS:000187127000006
URI http://repositorio.unifesp.br/handle/11600/27491

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