martes, 10 de abril de 2012

Differential Insulin Receptor Substrate-1 (IRS1)-Related Modulation of Neuropeptide Y and Proopiomelanocortin Expression in Nondiabetic and Diabetic IRS2−/− Mice

Differential Insulin Receptor Substrate-1 (IRS1)-Related Modulation of Neuropeptide Y and Proopiomelanocortin Expression in Nondiabetic and Diabetic IRS2−/− Mice


  • Diabetes-Insulin-Glucagon-Gastrointestinal

Differential Insulin Receptor Substrate-1 (IRS1)-Related Modulation of Neuropeptide Y and Proopiomelanocortin Expression in Nondiabetic and Diabetic IRS2−/− Mice

  1. Vicente Barrios
- Author Affiliations
  1. Department of Endocrinology (E.B.-R., S.C., E.B., L.M.F., J.A.C., J.A., V.B.), Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Department of Pediatrics, Universidad Autónoma de Madrid; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (E.B.-R., S.C., E.B., L.M.F., J.G.-A., G.F., J.A.C., J.A., V.B.), Instituto de Salud Carlos III; Instituto de Investigaciones Biomédicas Alberto Sols (A.G.-R., J.R.-C., A.M.V.), Consejo Superior de Investigaciones Cientificas/Universidad Autónoma de Madrid; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (A.G.-R., J.R.-C., A.M.V.), Instituto de Salud Carlos III, Madrid, E-28029, Spain; and Metabolic Research Laboratory (J.G.-A., G.F.), Clínica Universidad de Navarra, Pamplona, E-31008, Spain
  1. Address all correspondence and requests for reprints to: Vicente Barrios, Ph.D., Department of Endocrinology, Hospital Infantil Universitario Niño Jesús. Avda. Menéndez Pelayo, 65; E-28009 Madrid, Spain. E-mail: vbarrios@telefonica.net.

Abstract

Insulin resistance and type 2 diabetes correlate with impaired leptin and insulin signaling. Insulin receptor substrate-2 deficient (IRS2−/−) mice are an accepted model for the exploration of alterations in these signaling pathways and their relationship with diabetes; however, disturbances in hypothalamic signaling and the effect on neuropeptides controlling food intake remain unclear. Our aim was to analyze how leptin and insulin signaling may differentially affect the expression of hypothalamic neuropeptides regulating food intake and hypothalamic inflammation in diabetic (D) and nondiabetic (ND) IRS2−/− mice. We analyzed the activation of leptin and insulin targets by Western blotting and their association by immunoprecipitation, as well as the mRNA levels of neuropeptide Y (NPY), proopiomelanocortin, and inflammatory markers by real-time PCR and colocalization of forkhead box protein O1 (FOXO1) and NPY by double immunohistochemistry in the hypothalamus. Serum leptin and insulin levels and hypothalamic Janus kinase 2 and signal transducer and activator of transcription factor 3 activation were increased in ND IRS2−/− mice. IRS1 levels and its association with Janus kinase 2 and p85 and protein kinase B activation were increased in ND IRS2−/−. Increased FOXO1 positively correlated with NPY mRNA levels in D IRS2−/− mice, with FOXO1 showing mainly nuclear localization in D IRS2−/− and cytoplasmic in ND IRS2−/− mice. D IRS2−/− mice exhibited higher hypothalamic inflammation markers than ND IRS2−/− mice. In conclusion, differential activation of these pathways and changes in the expression of NPY and inflammation may exert a protective effect against hypothalamic deregulation of appetite, suggesting that manipulation of these targets could be of interest in the treatment of insulin resistance and type 2 diabetes.

Footnotes

  • For editorial see page 1010
  • Abbreviations:
    Akt
    Protein kinase B
    CD
    Cluster of differentiation
    D
    diabetic
    FOXO1
    forkhead box protein O1
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    JAK
    Janus kinase
    ND
    nondiabetic
    IRS
    insulin receptor substrate
    JNK
    c-Jun N-terminal kinase
    NEFA
    nonesterified fatty acids
    NFκB
    nuclear factor κB
    NPY
    neuropeptide Y
    ObRb
    long form of the leptin receptor
    PI3K
    phosphatidylinositol 3-kinase
    POMC
    proopiomelanocortin
    PTEN
    phosphatase and tensin homolog deleted on chromosome 10
    PTP1B
    tyrosine phosphatase type 1B
    RT
    reverse transcription
    SOCS
    suppressor of cytokine signaling
    STAT
    signal transducer and activator of transcription
    WT
    wild type

  • Received May 23, 2011.
  • Accepted December 2, 2011.

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