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Intracerebroventricular administration of neuropeptide Y induces hepatic insulin resistance via sympathetic innervation.

¹TNO-Quality of Life, Gaubius Laboratory, Leiden, The Netherlands
²Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
³Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
⁴Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
⁵Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
⁶Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

Objective: We recently showed that intracerebroventricular (ICV) infusion of neuropeptide Y 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 if ICV NPY administration modulates the suppressive action of insulin on EGP via hepatic sympathetic or parasympathetic innervation.

Research design and Methods: The effects of a continuous ICV infusion of NPY on glucose turnover were determined in rats during a hyperinsulinemic euglycemic clamp. Rats were either SHAM operated or the liver was sympathetically (HSx) or parasympathetically (HPx) denervated.

Results: Sympathectomy or parasympathectomy did not affect the capacity of insulin to suppress EGP in ICV vehicle-infused animals (50±8 vs. 49±6 vs. 55±6%, in HSx vs HPx vs SHAM, respectively). ICV 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 ICV NPY administration on insulin action to suppress EGP (NPY/HSx: 57±7%), whereas selective parasympathetic denervation had no effect (NPY/HPx: 29±7%).

Conclusions: ICV administration of NPY acutely induces insulin resistance of EGP via activation of sympathetic output to the liver.

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