title: Altered NK cell function in obese healthy humans.
abstract: BACKGROUND
  Obesity is associated with an elevated risk for several types of cancer and thus a major health hazard. However, the mechanism between overweight and cancer susceptibility is still elusive. Leptin, mainly produced by adipocytes links food intake and energy expenditure. In addition, recent studies have shown an immunomodulatory impact of leptin on NK cells. The purpose of the present study was to investigate whether leptin stimulation of NK cells from obese humans leads to altered functions as compared to NK cells from lean subjects. On the basis of body mass index 20 healthy individuals were classified in two groups: normal weight (<25 kg/m(2)) and obese (>30 kg/m(2)). Peripheral blood mononuclear cells (PBMC) were isolated from blood samples. We used flow cytometry to assess differences in phenotype and activity markers (CD107a, CD178 and TRAIL) of PBMCs between both groups. Furthermore, we determined after short-term in vitro leptin stimulation the phosphorylation of JAK2, downstream target of the intracellular signaling cascade of the leptin receptor, by Western Blotting and numbers of NK-cell-tumor-cell-conjugates as well as Granzyme(+) and IFN-γ(+) NK cells by flow cytometry. Finally, the proliferative capacity of control and long-term (7 days) leptin-stimulated NK cells was examined.
  
  
  RESULTS
  As opposed to similar NK cell counts, the number of CD3(+)CD56(+) cells was significantly lower in obese compared to lean subjects. Human NK cells express the leptin receptor (Ob-R). For further determination of Ob-R, intracellular target proteins of PBMCs were investigated by Western Blotting. Phosphorylation of JAK2 was lower in obese as compared to normal weight subjects. Furthermore, significantly lower levels of TNF-related apoptosis-inducing ligand (TRAIL) as an NK cell functional marker in obese subjects were found. In vitro leptin stimulation resulted in a higher production of interferon-γ in NK cells of normal weight subjects. Interestingly, long-term leptin stimulation had no significant influence on numbers of proliferating NK cells.
  
  
  CONCLUSIONS
  NK cells from obese healthy humans show functional deficits and altered responses after in vitro leptin challenge.
authors.affiliation: Institute for Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany ; Centre for Pediatrics and Adolescent Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Laue
authors.affiliation: Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA USA.
authors.forename: Christiane D
authors.initials: CD
authors.lastname: Wrann
authors.affiliation: Clinic for Pneumology, Hannover Medical School, Hannover, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Hoffmann-Castendiek
authors.affiliation: Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pietsch
authors.affiliation: Department of General-, Visceral-, Vascular and Thoracic Surgery, Charité, University Medicine Berlin, Campus Mitte, Berlin, Germany.
authors.forename: Lena
authors.initials: L
authors.lastname: Hübner
authors.affiliation: Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Kielstein
keywords: CD107a; Immunity; Leptin; Natural killer (NK) cells; Ob-R; Obesity; TRAIL