Central insulin action regulates peripheral glucose and fat metabolism in mice.

2.50
Hdl Handle:
http://hdl.handle.net/10541/66073
Title:
Central insulin action regulates peripheral glucose and fat metabolism in mice.
Authors:
Koch, Linda; Wunderlich, F Thomas; Seibler, Jost; Könner, A Christine; Hampel, Brigitte; Irlenbusch, Sigrid; Brabant, Georg E; Kahn, C Ronald; Schwenk, Frieder; Brüning, Jens C
Abstract:
Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.
Affiliation:
Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, and Center of Molecular Medicine Cologne, Cologne, Germany.
Citation:
Central insulin action regulates peripheral glucose and fat metabolism in mice. 2008, 118 (6):2132-47 J. Clin. Invest.
Journal:
The Journal of Clinical Investigation
Issue Date:
Jun-2008
URI:
http://hdl.handle.net/10541/66073
DOI:
10.1172/JCI31073
PubMed ID:
18451994
Type:
Article
Language:
en
ISSN:
0021-9738
Appears in Collections:
All Christie Publications ; Endocrinology

Full metadata record

DC FieldValue Language
dc.contributor.authorKoch, Linda-
dc.contributor.authorWunderlich, F Thomas-
dc.contributor.authorSeibler, Jost-
dc.contributor.authorKönner, A Christine-
dc.contributor.authorHampel, Brigitte-
dc.contributor.authorIrlenbusch, Sigrid-
dc.contributor.authorBrabant, Georg E-
dc.contributor.authorKahn, C Ronald-
dc.contributor.authorSchwenk, Frieder-
dc.contributor.authorBrüning, Jens C-
dc.date.accessioned2009-04-23T15:52:23Z-
dc.date.available2009-04-23T15:52:23Z-
dc.date.issued2008-06-
dc.identifier.citationCentral insulin action regulates peripheral glucose and fat metabolism in mice. 2008, 118 (6):2132-47 J. Clin. Invest.en
dc.identifier.issn0021-9738-
dc.identifier.pmid18451994-
dc.identifier.doi10.1172/JCI31073-
dc.identifier.urihttp://hdl.handle.net/10541/66073-
dc.description.abstractInsulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.en
dc.language.isoenen
dc.subjectInsulin Resistanceen
dc.subjectType 2 Diabetesen
dc.subjectMouse Modelsen
dc.subject.meshAdipose Tissue-
dc.subject.meshAnimals-
dc.subject.meshCentral Nervous System-
dc.subject.meshGene Deletion-
dc.subject.meshGene Expression Regulation-
dc.subject.meshGlucose-
dc.subject.meshHomozygote-
dc.subject.meshInsulin-
dc.subject.meshLipogenesis-
dc.subject.meshLipoprotein Lipase-
dc.subject.meshMice-
dc.subject.meshMice, Knockout-
dc.subject.meshModels, Biological-
dc.subject.meshModels, Genetic-
dc.subject.meshTissue Distribution-
dc.titleCentral insulin action regulates peripheral glucose and fat metabolism in mice.en
dc.typeArticleen
dc.contributor.departmentDepartment of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, and Center of Molecular Medicine Cologne, Cologne, Germany.en
dc.identifier.journalThe Journal of Clinical Investigationen

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