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Phosphoinositide-Specific Inositol Polyphosphate 5-Phosphatase IV Inhibits Inositide Trisphosphate Accumulation in Hypothalamus and Regulates Food Intake and Body Weight

Departments of Internal Medicine (D.F.B., E.P.A., M.C., G.R.S., J.B.C., M.J.A.S., L.A.V.), Medical Genetics (M.G.-C., I.L.-C.), and Physiology and Biophysics (M.H.T., A.C.B.), State University of Campinas, 13083-970 Campinas SP, Brazil; and Department of Physiology and Biophysics (J.V.C.F., L.C.M.) and Instituto do Coração (S.C.), University of Sao Paulo, 05508-900 São Paulo SP, Brazil

Address all correspondence and requests for reprints to: Licio A. Velloso, Departamento de Clínica Médica, Faculdade de Ciências Medicas, State University of Campinas, 13083-970 Campinas SP, Brazil. E-mail: lavelloso{at}fcm.unicamp.br.

The enzyme phosphatidylinositol 3-kinase (PI3-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 PI3-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 intracerebroventricular (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, insulin receptor substrate-2, and PI3-kinase. To evaluate the participation of 5ptase IV in insulin action in hypothalamus, we used a phosphorthioate-modified antisense oligonucleotide specific for this enzyme. The treatment of rats with this oligonucleotide for 4 d reduced the hypothalamic expression of 5ptase IV by approximately 80%. This was accompanied by an approximately 70% reduction of insulin-induced tyrosine phosphorylation of 5ptase IV and 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 and body weight loss. Thus, 5ptase IV is a powerful regulator of signaling through PI3-kinase in hypothalamus and may become an interesting target for therapeutics of obesity and related disorders.

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