Insulin Activation of Phosphatidylinositol 3-Kinase in the Hypothalamic Arcuate Nucleus
A Key Mediator of Insulin-Induced Anorexia
Kevin D. Niswender 1 ,
Christopher D. Morrison 1 ,
Deborah J. Clegg 2 ,
Ryan Olson 3 ,
Denis G. Baskin 1 4 ,
Martin G. Myers, Jr. 3 ,
Randy J. Seeley 2 and
Michael W. Schwartz 1
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.
Footnotes
Address correspondence and reprint requests to Michael W. Schwartz, Box 359757, Harborview Medical Center, 325 9th Ave., Seattle,
WA 98104. E-mail: mschwart{at}u.washington.edu .
Received for publication 2 October 2002 and accepted in revised form 13 November 2002.
Posted on the World Wide Web at http://diabetes.diabetesjournals.org on 6 December 2002.
K.D.N. and C.D.M. contributed equally to this study.
D.J.C. and R.J.S. have received research funding from Procter and Gamble. M.W.S. is a member of the Scientific Advisory Board
for Millennium Pharmaceuticals and Amylin Pharmaceuticals and has received honoraria from Eli Lilly.
IRS, insulin receptor substrate;...

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

10.2337/diabetes.52.2.227