Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity.

2.50
Hdl Handle:
http://hdl.handle.net/10541/65702
Title:
Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity.
Authors:
Nave, Heike; Mueller, Guenter; Siegmund, Britta; Jacobs, Roland; Stroh, Thorsten; Schueler, Ulrike; Hopfe, Matthias; Behrendt, Patrick; Buchenauer, Tobias; Pabst, Reinhard; Brabant, Georg E
Abstract:
Leptin acts not only as an anorexigenic hormone but also regulates cell-mediated immunity via leptin receptors (Ob-R) expressed on T and B lymphocytes. However, the impact of leptin on natural killer (NK) cells is currently elusive. We evaluated leptin effects on NK cells in relation to the body weight in rats using in vivo and in vitro approaches. Leptin was injected iv in male lean and diet-induced obese Lewis and F344 rats. NK cell numbers were analyzed in blood and spleen by fluorescence activated cell sorting and immunohistochemistry, and the activity of NK cells was measured by chromium release assay. Ob-R expression was investigated by confocal laser scanning and quantitative RT-PCR. To compare leptin-dependent intracellular signaling under basal and leptin- and tumor cell (MADB106)-stimulated conditions, intracellular target proteins of NK cells were evaluated by Western blotting. Number and distribution pattern of splenic NK cells were significantly different in lean and obese animals. Leptin administration resulted in a 4-fold higher stimulation of the NK activity in lean than obese animals. This was not due to a decreased expression of Ob-R because quantitative RT-PCR revealed significantly higher Ob-Rb mRNA levels in NK cells from obese rats. In contrast, postreceptor signaling is differentially abrogated in obese animals with significantly lower activation of postreceptor signaling components (Janus kinase-2p, protein kinase B pT308, AMPalphapT172) after an in vivo leptin challenge. In conclusion, the results for the first time assign leptin a central role as a modulator of NK cell number and activity only in lean but not obese subjects. The differential role of leptin has important implications for the influence of body weight in the response to systemic inflammations and in the immunological defense of cancer.
Affiliation:
Institute for Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. nave.heike@mh-hannover.de
Citation:
Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity. 2008, 149 (7):3370-8 Endocrinology
Journal:
Endocrinology
Issue Date:
Jul-2008
URI:
http://hdl.handle.net/10541/65702
DOI:
10.1210/en.2007-1516
PubMed ID:
18356278
Type:
Article
Language:
en
ISSN:
0013-7227
Appears in Collections:
All Christie Publications ; Endocrinology

Full metadata record

DC FieldValue Language
dc.contributor.authorNave, Heike-
dc.contributor.authorMueller, Guenter-
dc.contributor.authorSiegmund, Britta-
dc.contributor.authorJacobs, Roland-
dc.contributor.authorStroh, Thorsten-
dc.contributor.authorSchueler, Ulrike-
dc.contributor.authorHopfe, Matthias-
dc.contributor.authorBehrendt, Patrick-
dc.contributor.authorBuchenauer, Tobias-
dc.contributor.authorPabst, Reinhard-
dc.contributor.authorBrabant, Georg E-
dc.date.accessioned2009-04-21T17:12:43Z-
dc.date.available2009-04-21T17:12:43Z-
dc.date.issued2008-07-
dc.identifier.citationResistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity. 2008, 149 (7):3370-8 Endocrinologyen
dc.identifier.issn0013-7227-
dc.identifier.pmid18356278-
dc.identifier.doi10.1210/en.2007-1516-
dc.identifier.urihttp://hdl.handle.net/10541/65702-
dc.description.abstractLeptin acts not only as an anorexigenic hormone but also regulates cell-mediated immunity via leptin receptors (Ob-R) expressed on T and B lymphocytes. However, the impact of leptin on natural killer (NK) cells is currently elusive. We evaluated leptin effects on NK cells in relation to the body weight in rats using in vivo and in vitro approaches. Leptin was injected iv in male lean and diet-induced obese Lewis and F344 rats. NK cell numbers were analyzed in blood and spleen by fluorescence activated cell sorting and immunohistochemistry, and the activity of NK cells was measured by chromium release assay. Ob-R expression was investigated by confocal laser scanning and quantitative RT-PCR. To compare leptin-dependent intracellular signaling under basal and leptin- and tumor cell (MADB106)-stimulated conditions, intracellular target proteins of NK cells were evaluated by Western blotting. Number and distribution pattern of splenic NK cells were significantly different in lean and obese animals. Leptin administration resulted in a 4-fold higher stimulation of the NK activity in lean than obese animals. This was not due to a decreased expression of Ob-R because quantitative RT-PCR revealed significantly higher Ob-Rb mRNA levels in NK cells from obese rats. In contrast, postreceptor signaling is differentially abrogated in obese animals with significantly lower activation of postreceptor signaling components (Janus kinase-2p, protein kinase B pT308, AMPalphapT172) after an in vivo leptin challenge. In conclusion, the results for the first time assign leptin a central role as a modulator of NK cell number and activity only in lean but not obese subjects. The differential role of leptin has important implications for the influence of body weight in the response to systemic inflammations and in the immunological defense of cancer.en
dc.language.isoenen
dc.subjectLeptin Resistanceen
dc.subjectCell Dysfunctionen
dc.subjectCell Line, Tumour-
dc.subject.meshAnimals-
dc.subject.meshCell Count-
dc.subject.meshCell Line, Tumor-
dc.subject.meshDietary Carbohydrates-
dc.subject.meshDietary Fats-
dc.subject.meshFlow Cytometry-
dc.subject.meshImmunoblotting-
dc.subject.meshInjections, Intravenous-
dc.subject.meshJanus Kinase 2-
dc.subject.meshKiller Cells, Natural-
dc.subject.meshLeptin-
dc.subject.meshMale-
dc.subject.meshMicroscopy, Confocal-
dc.subject.meshObesity-
dc.subject.meshRats-
dc.subject.meshRats, Inbred F344-
dc.subject.meshRats, Inbred Lew-
dc.subject.meshReceptors, Leptin-
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction-
dc.subject.meshSignal Transduction-
dc.subject.meshSpleen-
dc.titleResistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity.en
dc.typeArticleen
dc.contributor.departmentInstitute for Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. nave.heike@mh-hannover.deen
dc.identifier.journalEndocrinologyen

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