Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in Agouti-Related Protein and POMC Neurons
- Hua V. Lin1,
- Leona Plum1,
- Hiraku Ono2,
- Roger Gutiérrez-Juárez2,
- Marya Shanabrough3,
- Erzsebet Borok3,
- Tamas L. Horvath3,
- Luciano Rossetti2 and
- Domenico Accili1
- 1Department of Medicine, Columbia University, New York, New York;
- 2Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York;
- 3Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut.
- Corresponding author: Domenico Accili, da230{at}columbia.edu.
Abstract
OBJECTIVE The sites of insulin action in the central nervous system that regulate glucose metabolism and energy expenditure are incompletely characterized. We have shown that mice with hypothalamic deficiency (L1) of insulin receptors (InsRs) fail to regulate hepatic glucose production (HGP) in response to insulin.
RESEARCH DESIGN AND METHODS To distinguish neurons that mediate insulin's effects on HGP from those that regulate energy homeostasis, we used targeted knock-ins to express InsRs in agouti-related protein (AgRP) or proopiomelanocortin (POMC) neurons of L1 mice.
RESULTS Restoration of insulin action in AgRP neurons normalized insulin suppression of HGP. Surprisingly, POMC-specific InsR knock-in increased energy expenditure and locomotor activity, exacerbated insulin resistance and increased HGP, associated with decreased expression of the ATP-sensitive K+ channel (KATP channel) sulfonylurea receptor 1 subunit, and decreased inhibitory synaptic contacts on POMC neurons.
CONCLUSIONS The contrasting phenotypes of InsR knock-ins in POMC and AgRP neurons suggest a branched-pathway model of hypothalamic insulin signaling in which InsR signaling in AgRP neurons decreases HGP, whereas InsR activation in POMC neurons promotes HGP and activates the melanocortinergic energy expenditure program.
Footnotes
-
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
- Received September 2, 2009.
- Accepted November 6, 2009.
- © 2010 by the American Diabetes Association.
