Leptin as a modulator of glial activity in inflammation

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The adipocyte derived circulating hormone leptin, acts on hypothalamic neurons to regulate energy balance by suppressing appetite and increasing energy expenditure. Recent discoveries have demonstrated that leptin also affects other biological systems including immunity. Several studies have now demonstrated complex and direct interactions between leptin and immune mediators, most notably cytokines such as interleukin (IL)-1, both in the periphery and the brain. Previously we demonstrated a functional link between leptin and brain IL-1ß by showing, that the appetite suppressing effects of this hormone were mediated via the induction of this cytokine. In addition we reported that leptin could trigger other brain-orchestrated responses synonymous with the host’s response to exogenous pathogenic exposure including fever, an effect that is also IL-1ß dependent. This was the first evidence directly linking leptin with ‘sickness’ type behaviours, which led to our original hypothesis that it could act as a classical peripheral inflammatory signal to the brain. We subsequently confirmed this by neutralizing endogenous leptin, in animals treated with the bacterial lipopolysaccharide (LPS), a potent activator of pro-inflammatory cytokines in the periphery and the brain. This led to a suppression of the LPS induced sickness responses, which were accompanied with the attenuation of hypothalamic IL-1ß expression. 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 over 24h rendered the cells more reactive to secondary inflammatory stimuli such as LPS, which resulted in a several-fold increase in IL-1ß output in the culture medium. This effect was not limited to IL-1ß but was also true for other cytokines and chemokines. The role of leptin in potentiating the microglial response to LPS appeared to be linked to morphological changes involving the cytoskeletal component actin. In addition, using a time lapse study to monitor these morphological changes over an extended period of time we showed that the effects of leptin were long lasting (up to 96 h) with the microglia remaining fully viable compared to the untreated and LPS treated cells which had undergone cell death 72 h into the study. Other than its direct effect on microglia our most recent discoveries have linked this hormone with the modulation of IL-1ß expressing neutrophil trafficking into the brain to propagate the inflammatory response, a process that we believe involves chemokine production by microglia. Cumulatively these preliminary observations led us to hypothesize that the role of leptin in immunity is that of a modulator of immune cell activity in the brain, which may include the orchestration of the inflammatory response via the promotion of cell to cell interactions. Because circulating leptin levels fluctuate across a multitude of conditions (e.g. obesity, anorexia) a role for this hormone in modulating immune cell function in the brain could have wide-ranging implications for neuro-inflammatory responses. Thus to address this hypothesis we will conduct both in vivo and in vitro approaches in mice to investigate: 1. how leptin modulates microglial viability and survival, 2. if preconditioning by high or low levels of the hormone (as found in obese or food restricted animals respectively) affect the microglial responses to immunogenic stimuli, 3. whether neutrophil borne IL-ß activates microglial cells.