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Divergent Regulation of Energy Expenditure and Hepatic Glucose Production by Insulin Receptor in Agouti-Related Protein and POMC Neurons.

Authors :
Lin, Hua V.
Plum, Leona
Ono, Hiraku
Gutiérrez-Juárez, Roger
Shanabrough, Marya
Borok, Erzsebet
Horvath, Tamas L.
Rossetti, Luciano
Accili, Domenico
Source :
Diabetes; Feb2010, Vol. 59 Issue 2, p337-346, 10p, 1 Diagram, 1 Chart, 5 Graphs
Publication Year :
2010

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[sup +] channel (K[sub ATP] channel) sulfonylurea receptor 1 subunit, and decreased inhibitory synaptic contacts on POMC neurons. CONCLUSIONS--The contrasting phenotypes of InsR knockins 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. Diabetes 59:337-346, 2010 [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00121797
Volume :
59
Issue :
2
Database :
Complementary Index
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
48595537
Full Text :
https://doi.org/10.2337/db09-1303