Intracerebroventricular administration of neuropeptide Y induces hepatic insulin resistance via sympathetic innervation.
OBJECTIVE
We recently showed that intracerebroventricular infusion of neuropeptide Y (NPY) hampers inhibition of endogenous glucose production (EGP) by insulin in mice. The downstream mechanisms responsible for these effects of NPY remain to be elucidated. Therefore, the aim of this study was to establish whether intracerebroventricular NPY administration modulates the suppressive action of insulin on EGP via hepatic sympathetic or parasympathetic innervation.


METHODS
The effects of a continuous intracerebroventricular infusion of NPY on glucose turnover were determined in rats during a hyperinsulinemic-euglycemic clamp. Either rats were sham operated, or the liver was sympathetically (hepatic sympathectomy) or parasympathetically (hepatic parasympathectomy) denervated.


RESULTS
Sympathectomy or parasympathectomy did not affect the capacity of insulin to suppress EGP in intracerebroventricular vehicle-infused animals (50 +/- 8 vs. 49 +/- 6 vs. 55 +/- 6%, in hepatic sympathectomy vs. hepatic parasympathectomy vs. sham, respectively). Intracerebroventricular infusion of NPY significantly hampered the suppression of EGP by insulin in sham-denervated animals (29 +/- 9 vs. 55 +/- 6% for NPY/sham vs. vehicle/sham, respectively, P = 0.038). Selective sympathetic denervation of the liver completely blocked the effect of intracerebroventricular NPY administration on insulin action to suppress EGP (NPY/hepatic sympathectomy, 57 +/- 7%), whereas selective parasympathetic denervation had no effect (NPY/hepatic parasympathectomy, 29 +/- 7%).


CONCLUSIONS
Intracerebroventricular administration of NPY acutely induces insulin resistance of EGP via activation of sympathetic output to the liver.
TNO-Quality of Life, Gaubius Laboratory, Leiden, the Netherlands. a.vandenhoek@tno.nl
Anita M
AM
van den Hoek
Caroline
C
van Heijningen
Janny P
JP
Schröder-van der Elst
D Margriet
DM
Ouwens
Louis M
LM
Havekes
Johannes A
JA
Romijn
Andries
A
Kalsbeek
Hanno
H
Pijl
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007276:Injections, Intraventricular; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000294:innervation / Q000378:metabolism*; D008297:Male; D009478:Neuropeptide Y / Q000494:pharmacology* / Q000502:physiology*; D017764:Parasympathectomy; D051381:Rats; D017208:Rats, Wistar; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009478:Neuropeptide Y