Leptin is a pleiotropic cytokine/hormone that has been shown to primarily play a critical role on food intakeand energy expenditure but is also a participant in functions of the immune system, including that of antigenpresenting cells (APCs). Of the three cell populations that constitute APCs, only one, dendritic cells (DC)have the ability to initiate naive T cell responses. Our goal is to assess the potential role of leptin on DCfunction particularly when signaling through the leptin receptor is compromised, such as in patients afflictedwith obesity or Type II Diabetes. We have found, analyzing DC isolated and enriched from spleens of leptindeficientmice (Lepob), that some, but not all, of DC functions are affected when compared to splenic DC fromcontrol C57BI/6 mice. Preliminary data has shown that DC do express the long isoform of the leptin receptorand therefore can be responsive to leptin. Leptin-deficiency does not alter DC phenotype, DC activation byinflammatory stimuli, or processing of antigen; however, leptin-deficiency does affect DC ability to acquireantigen and to effectively activate T cells. We have also found that the addition of exogenous leptin to bonemarrow-derived DC alters the morphology of the DC, promoting more and longer extensions and alsoenhances DC survival. We hypothesize that leptin signaling is reduced in DC from leptin-deficient mice dueto a reduction in leptin receptor density and that normally, leptin enhances DC survival and dendriteformation thereby enhancing APC - T cell interactions leading to optimal T cell activation. We propose toaddress our hypothesis with three specific aims.
Aim 1 will determine the relative expression levels of theong isoform of the leptin receptor on DC using standard Western blot analysis and Q-PCR.
Aim 2 willascertain if leptin enhances DC survival when in co-culture with T cells by assessing the induction of DCapoptosis and will ascertain if leptin enhances DC - T cell conjugate formation by a number of microscopytechniques. Lastly, Aim 3 will evaluate the induction of signaling events in DC by leptin. More specifically,the induction of pro-survival signaling pathways will be evaluated biochemically and the induction of actin reorganizationwill be assessed via microscopy and biochemical assays. Considering the potential influence ofeptin on DC maturation and function (as suggested by our preliminary data), resistance to leptin signalingtiat occurs in the obese and in type 2 diabetes may compromise DC function and thus T cell-mediatedmmunity underscoring the clinical significance of understanding the role of leptin in immunity.
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