Leptin as a modulator of glial function in inflammation

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The adipocyte derived energy regulating hormone, leptin is now established as an important interface between the energy status of an organism and its ability to mount an ***effective host defense response against invading pathogens. This role is linked to the recently described function of this hormone as an immune modulator and an important regulator of immunity both in the periphery and the brain. We were amongst the first to describe a direct functional relationship between leptin and pro-inflammatory cytokines such as brain interleukin (IL)- 1ß by showing, that the appetite suppressing effects of this hormone were mediated via the induction of this cytokine in the brain. In subsequent in vitro studies we identified the cellular targets of leptin in the brain for the induction of IL-1 to be microglia, which we have shown to express the functional leptin receptor. In addition to the direct induction of IL-1 we discovered that pre-incubation of primary microglial cells in culture with leptin rendered the cells more reactive to secondary immunogenic stimuli such as bacterial lipopolysaccharide (LPS), which resulted in a several-fold increase in IL-1ß output in the culture medium. This effect appeared to be linked to morphological changes induced by leptin. Given this apparent modulatory effect of leptin on microglial function, we are currently testing the hypothesis that the prolonged exposure of these cells to higher than normal concentrations of this hormone, such as occurs following prolonged consumption of high fat diet (HFD), will results in a fundamental, and possibly irreversible, shift in their normal activity and cell cycle. In recent experiments we have confirmed that the consumption of HFD for 1 or 3 weeks induces higher circulating levels of leptin and results in significant activation of microglia. This increased activity, was accompanied by upregulations in the expression of proteins linked with microglial phagocytosis, was particularly intense in regions known for significant adult neurogenic activity, including the hypothalamus and hippocampus. Using Nestin-GFP positive mice we in addition observed a significant HFD induced increase in the expression of Nestin (marker for new born neurons) positive cells in the same regions. We now intend to investigate if the higher activity of microglia is functionally linked to phagocytosis of newborn cells in these regions and the consequences of these events. For this we will use a multidisciplinary technical approach including cutting edge imaging techniques and a number of transgenic mouse lines including the obese leptin (ob/ob) deficient mice.**