Previous studies demonstrated that lymphocyte development is impaired in leptin receptor (Ob‐R)‐deficient db/db mice. However, it remains unclear whether or not leptin signaling plays a physiological role in dendritic cell (DC) development and function. In this study, we first detected Ob‐R expression in murine DC. Using db/db mice at a pre‐diabetic stage, we demonstrate that the total number of DC generated from bone marrow (BM) cultures is significantly lower than in WT controls. Similarly, selective blockade of leptin with a soluble mouse Ob‐R chimera (Ob‐R:Fc) inhibited DC generation in wild‐type BM cultures. The reduced DC yield in db/db BM culture was attributed to significantly increased apoptosis, which was associated with dysregulated expression of Bcl‐2 family genes. Moreover, db/db DC displayed markedly reduced expression of co‐stimulatory molecules and a Th2‐type cytokine profile, with a poor capacity to stimulate allogeneic T cell proliferation. Consistent with their impaired DC phenotype and function, db/db DC showed significantly down‐regulated activities of the PI3K/Akt pathway as well as STAT‐3 and IκB‐α. In conclusion, our findings demonstrate the involvement of leptin signaling in DC survival and maturation.

See accompanying commentary: http://dx.doi.org/10.1002/eji.200636770