The metabolic syndrome in mice overexpressing neuropeptide Y in noradrenergic neurons

    1. Eriika Savontaus7
    1. 1Institute of Biomedicine and Turku Center for Disease Modelling; Drug Research Doctoral Program, University of Turku, Turku, Finland
    2. 2Institute of Biomedicine and Turku Center for Disease Modelling, University of Turku, Turku, Finland
    3. 3Department of Pathology, University of Turku and Turku University Hospital, Turku, Finland
    4. 4Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland
    5. 5Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
    6. 6Department of Internal Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
    7. 7Institute of Biomedicine and Turku Center for Disease Modelling, University of Turku; Turku University Hospital, Unit of Clinical Pharmacology, Turku, Finland
    1. Correspondence should be addressed to E Savontaus; Email: eriika.savontaus{at}


    A gain-of-function polymorphism in human neuropeptide Y (NPY) gene (rs16139) associates with metabolic disorders and earlier onset of type 2 diabetes (T2D). Similarly, mice overexpressing NPY in noradrenergic neurons (OE-NPYDBH) display obesity and impaired glucose metabolism. In this study, the metabolic syndrome-like phenotype was characterized and mechanisms of impaired hepatic fatty acid, cholesterol and glucose metabolism in pre-obese (2-month-old) and obese (4–7-month-old) OE-NPYDBH mice were elucidated. Susceptibility to T2D was assessed by subjecting mice to high caloric diet combined with low-dose streptozotocin. Contribution of hepatic Y1-receptor to the phenotype was studied using chronic treatment with an Y1-receptor antagonist, BIBO3304. Obese OE-NPYDBH mice displayed hepatosteatosis and hypercholesterolemia preceded by decreased fatty acid oxidation and accelerated cholesterol synthesis. Hyperinsulinemia in early obese state inhibited pyruvate- and glucose-induced hyperglycemia, and deterioration of glucose metabolism of OE-NPYDBH mice developed with aging. Furthermore, streptozotocin induced T2D only in OE-NPYDBH mice. Hepatic inflammation was not morphologically visible, but upregulated hepatic anti-inflammatory pathways and increased 8-isoprostane combined with increased serum resistin and decreased interleukin 10 pointed to increased NPY-induced oxidative stress that may predispose OE-NPYDBH mice to insulin resistance. Chronic treatment with BIBO3304 did not improve the metabolic status of OE-NPYDBH mice. Instead, downregulation of beta-1-adrenoceptors suggests indirect actions of NPY via inhibition of sympathetic nervous system. In conclusion, changes in hepatic fatty acid, cholesterol and glucose metabolism favoring energy storage contribute to the development of NPY-induced metabolic syndrome, and the effect is likely mediated by changes in sympathetic nervous system activity.

    • Received 28 March 2017
    • Accepted 3 May 2017
    • Made available online as an Accepted Preprint 3 May 2017
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