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

Heike Nave, Guenter Mueller, Britta Siegmund, Roland Jacobs, Thorsten Stroh, Ulrike Schueler, Matthias Hopfe, Patrick Behrendt, Tobias Buchenauer, Reinhard Pabst, Georg Brabant

    Research output: Contribution to journalArticlepeer-review


    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. Numberand 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, AMPαpT172) 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. Copyright © 2008 by The Endocrine Society.
    Original languageEnglish
    Pages (from-to)3370-3378
    Number of pages8
    Issue number7
    Publication statusPublished - Jul 2008


    • Animals
    • Cell Count
    • Cell Line, Tumor
    • administration & dosage: Dietary Carbohydrates
    • administration & dosage: Dietary Fats
    • Flow Cytometry
    • Immunoblotting
    • Injections, Intravenous
    • metabolism: Janus Kinase 2
    • drug effects: Killer Cells, Natural
    • administration & dosage: Leptin
    • Male
    • Microscopy, Confocal
    • etiology: Obesity
    • Rats
    • Rats, Inbred F344
    • Rats, Inbred Lew
    • genetics: Receptors, Leptin
    • Reverse Transcriptase Polymerase Chain Reaction
    • drug effects: Signal Transduction
    • cytology: Spleen


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