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Intracerebroventricular Neuropeptide Y Infusion Precludes Inhibition of Glucose and VLDL Production by Insulin

¹ Organization of Applied Scientific Research-Prevention and Health, Gaubius Laboratory, Leiden, the Netherlands
² Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
³ Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, the Netherlands
⁴ Netherlands Institute for Brain Research, Amsterdam, the Netherlands
⁵ Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands

Recent evidence demonstrates that hypothalamic insulin signaling is required for inhibition of endogenous glucose production. The downstream mechanisms that are responsible for the effects of hypothalamic insulin receptor activation on hepatic fuel flux remain to be determined. To establish whether downregulation of neuropeptide Y (NPY) release by insulin is mandatory for its capacity to suppress glucose production, we examined the effects of a continuous intracerebroventricular (ICV) infusion of NPY (10 µg/h for 3–5 h) on glucose flux during a hyperinsulinemic-euglycemic clamp in mice. We also evaluated the effects of ICV NPY administration on free fatty acid and glycerol flux and VLDL production in this experimental context. In basal conditions, none of the metabolic parameters was affected by NPY infusion. In hyperinsulinemic conditions, peripheral glucose disposal was not different between vehicle- and NPY-infused animals. In contrast, hyperinsulinemia suppressed endogenous glucose production by 8% vs. 30% in NPY- vs. vehicle-infused mice, respectively (P < 0.05). Also, VLDL production was significantly higher during hyperinsulinemia in NPY- compared with vehicle-infused mice (97.5 ± 18.0 vs. 54.7 ± 14.9 µmol · kg^–1 · h^–1; P < 0.01). These data suggest that the neurophysiological action of insulin to downregulate hypothalamic NPY release is a prerequisite for its ability to suppress hepatic fuel production, whereas it is not mandatory for its capacity to modulate glucose disposal or lipolysis.

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