Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats |
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Authors: | J?B?C?Carvalheira E?B?Ribeiro E?P?Araújo R?B?Guimar?es M?M?Telles M?Torsoni J?A?R?Gontijo L?A?Velloso Email author" target="_blank">M?J?A?SaadEmail author |
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Institution: | (1) Departamento de Clínica Médica, FCM, Universidade Estadual de Campinas (UNICAMP), 13081-970 Campinas, SP, Brasil;(2) Departamento de Fisiologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brasil |
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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.Abbreviations ERK
extracellular signal-regulated kinase
- Grb2
growth factor receptor binding protein 2
- IR
insulin receptor
- IRS
insulin receptor substrate
- MAPK
mitogen-activated protein kinase
- PI 3-kinase
phosphatidylinositol 3-kinase
- PKC
Protein kinase C
- Shc
Src-homology and collagen homology
- SHP2
Src-homology phosphatase 2
- TNF-
Tumor-necrosis factor-![agr](/content/g9lea52blrlx4q6g/xxlarge945.gif) |
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Keywords: | Obesity insulin resistance hypothalamus anorexia signal transduction phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism mitogen-activated protein kinase |
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