Advanced search
Start date
Betweenand


Involved molecular mechanisms in the control of the alimentary ingestion and the corporal weight-participation of 5PTASE IV

Full text
Author(s):
Daniela Faleiros Bertelli
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
Defense date:
Examining board members:
Licio Augusto Velloso; Eliane Beraldi Ribeiro; Jose Antonio Rocha Gontijo; Francesco Langone; Marcio Alberto Torsoni
Advisor: Licio Augusto Velloso
Abstract

The enzyme phosphatidylinositol 3-kinase (PI 3-kinase) exerts an important role in the transduction of the anorexigenic and thermogenic signals delivered by insulin and leptin to first-order neurons of the arcuate nucleus in the hypothalamus. The termination of the intracellular signals generated by the activation of PI 3-kinase depends on the coordinated activity of specific inositol phosphatases. Here, we show that phosphoinositide-specific inositol polyphosphate 5-phosphatase IV (5ptase IV) is highly expressed in neurons of the arcuate and lateral nuclei of the hypothalamus. Upon intracerebroventicular (ICV) treatment with insulin, 5ptase IV undergoes a time-dependent tyrosine phosphorylation, which follows the same patterns of canonical insulin signaling through the insulin receptor, IRS-2, and PI 3-kinase. To evaluate the participation of 5ptase IV in insulin action in hypothalamus, we employed a phosphorthioate modified antisense oligonucleotide specific for this enzyme. The treatment of rats with this oligonucleotide for four days reduced the hypothalamic expression of 5ptase IV by ~80%. This was accompanied by a ~70% reduction of insulin-induced tyrosine phosphorylation of 5ptase IV and by an increase in basal accumulation of phosphorylated inositols in the hypothalamus. Finally, inhibition of hypothalamic 5ptase IV expression by the antisense approach resulted in reduced daily food intake, body weight loss and decreased 12 h spontaneous food intake. Thus, 5ptase IV is a powerful regulator of signaling through PI 3-kinase in hypothalamus and may become an interesting target for therapeutics of obesity and related disorders (AU)