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Differential insulin receptor substrate-1 (IRS1)-related modulation of neuropeptide Y and proopiomelanocortin expression in nondiabetic and diabetic IRS2-/- mice

AuthorsGonzález-Rodríguez, Águeda; Frago, Laura M.; Revuelta-Cervantes, Jesús; Valverde, Ángela M.
Issue Date2012
PublisherEndocrine Society
CitationEndocrinology 153(3): 1129-1140 (2012)
AbstractInsulin 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 intakeandhypothalamic 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 transducerandactivator of transcription factor 3 activation were increased inNDIRS2 -/-mice. IRS1 levelsandits association with Janus kinase 2andp85andprotein kinaseBactivation were increased inNDIRS2 -/-. Increased FOXO1 positively correlated with NPYmRNAlevels inDIRS2 -/-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 couldbeof interest in the treatment of insulin resistance and type 2 diabetes. Copyright © 2012 by The Endocrine Society.
Description12 páginas, 8 figuras.-- et al.
Publisher version (URL)http://dx.doi.org/10.1210/en.2011-1278
Identifiersdoi: 10.1210/en.2011-1278
issn: 0013-7227
e-issn: 1945-7170
Appears in Collections:(IIBM) Artículos
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