Glucocorticoid signaling in the arcuate nucleus modulates hepatic insulin sensitivity.
Glucocorticoid receptors are highly expressed in the hypothalamic paraventricular nucleus (PVN) and arcuate nucleus (ARC). As glucocorticoids have pronounced effects on neuropeptide Y (NPY) expression and as NPY neurons projecting from the ARC to the PVN are pivotal for balancing feeding behavior and glucose metabolism, we investigated the effect of glucocorticoid signaling in these areas on endogenous glucose production (EGP) and insulin sensitivity by local retrodialysis of the glucocorticoid receptor agonist dexamethasone into the ARC or the PVN, in combination with isotope dilution and hyperinsulinemic-euglycemic clamp techniques. Retrodialysis of dexamethasone for 90 min into the ARC or the PVN did not have significant effects on basal plasma glucose concentration. During the hyperinsulinemic-euglycemic clamp, retrodialysis of dexamethasone into the ARC largely prevented the suppressive effect of hyperinsulinemia on EGP. Antagonizing the NPY1 receptors by intracerebroventricular infusion of its antagonist largely blocked the hepatic insulin resistance induced by dexamethasone in the ARC. The dexamethasone-ARC-induced inhibition of hepatic insulin sensitivity was also prevented by hepatic sympathetic denervation. These data suggest that glucocorticoid signaling specifically in the ARC neurons modulates hepatic insulin responsiveness via NPY and the sympathetic system, which may add to our understanding of the metabolic impact of clinical conditions associated with hypercortisolism.
Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, the Netherlands. yica@ucmail.uc.edu
Chun-Xia
CX
Yi
Ewout
E
Foppen
William
W
Abplanalp
Yuanqing
Y
Gao
Anneke
A
Alkemade
Susanne E
SE
la Fleur
Mireille J
MJ
Serlie
Eric
E
Fliers
Ruud M
RM
Buijs
Matthias H
MH
Tschöp
Andries
A
Kalsbeek
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000294:innervation / Q000378:metabolism*; D008297:Male; D009478:Neuropeptide Y / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013562:Sympathectomy
D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D003907:Dexamethasone; D005947:Glucose