Insulin Activation of Phosphatidylinositol 3-Kinase in the Hypothalamic Arcuate Nucleus

Author:

Niswender Kevin D.1,Morrison Christopher D.1,Clegg Deborah J.2,Olson Ryan3,Baskin Denis G.14,Myers Martin G.3,Seeley Randy J.2,Schwartz Michael W.1

Affiliation:

1. Division of Metabolism, Endocrinology and Nutrition, University of Washington School of Medicine and Harborview Medical Center, Seattle, Washington

2. Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio

3. Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts

4. Puget Sound Veterans Affairs Medical Center, Seattle, Washington

Abstract

In peripheral tissues, insulin signaling involves activation of the insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI3K) enzyme system. In the hypothalamus, insulin functions with leptin as an afferent adiposity signal important for the regulation of body fat stores and hepatic glucose metabolism. To test the hypothesis that hypothalamic insulin action involves intracellular PI3K signaling, we used histochemical and biochemical methods to determine the effect of insulin on hypothalamic IRS-PI3K activity. Here, we report that insulin induces tyrosine phosphorylation of the insulin receptor and IRS-1 and -2, increases binding of activated IRS-1 and -2 to the regulatory subunit of PI3K, and activates protein kinase B/Akt, a downstream target of PI3K. Using an immunohistochemical technique to detect PI 3,4,5-triphosphate, the main product of PI3K activity, we further demonstrate that in the arcuate nucleus, insulin-induced PI3K activity occurs preferentially within cells that contain IRS-2. Finally, we show that the food intake- lowering effects of insulin are reversed by intracerebroventricular infusion of either of two PI3K inhibitors at doses that have no independent feeding effects. These findings support the hypothesis that the IRS-PI3K pathway is a mediator of insulin action in the arcuate nucleus and, combined with recent evidence that leptin activates PI3K signaling in the hypothalamus, provide a plausible mechanism for neuronal cross-talk between insulin and leptin signaling.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

Reference25 articles.

1. Saltiel AR, Pessin JE: Insulin signaling pathways in time and space. Trends Cell Biol 12:65–71,2002

2. Niswender KD, Gallis B, Blevins JE, Corson MA, Schwartz MW, Baskin DG: Immunocytochemical detection of phosphatidylinositol 3-kinase activation by insulin and leptin. J Histochem Cytochem. In press

3. Wolkow CA, Kimura KD, Lee MS, Ruvkun G: Regulation of C. elegans life-span by insulinlike signaling in the nervous system. Science 290:147–150,2000

4. Garofalo RS: Genetic analysis of insulin signaling in Drosophila. Trends Endocrinol Metab 13:156–162,2002

5. Niswender KD, Schwartz MW: Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities. Front Neuroendocrinol. In press

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