Divergent regulation of energy expenditure and hepatic glucose production by insulin receptor in agouti-related protein and POMC neurons.
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.


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 (K(ATP) 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.
Lin
Hua V
HV
Department of Medicine, Columbia University, New York, New York, USA. da230@columbia.edu
Plum
Leona
L
Ono
Hiraku
H
Gutiérrez-Juárez
Roger
R
Shanabrough
Marya
M
Borok
Erzsebet
E
Horvath
Tamas L
TL
Rossetti
Luciano
L
Accili
Domenico
D
D054369:Agouti-Related Protein / Q000502:physiology*; D000818:Animals; D001835:Body Weight; D017931:DNA Primers; D002149:Energy Intake; D004734:Energy Metabolism; D005215:Fasting; D005934:Glucagon / Q000097:blood; D005947:Glucose / Q000096:biosynthesis*; D015309:Glucose Clamp Technique; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D054369:Agouti-Related Protein; D017931:DNA Primers; D007328:Insulin; D012313:RNA; D011333:Pro-Opiomelanocortin; D005934:Glucagon; D011972:Receptor, Insulin; D005947:Glucose