Leptin as a modulator of glial activity in inflammation

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Communication between the immune system and the brain is a critical process governing our ability to respond to and mount an effective defense response against invading pathogens. Peripheral immune mediators known as cytokines (e.g. interleukin-1) play an important role in this communication through direct actions in the brain. We have shown previously that a new member of this family, leptin, which is mainly produced by fat in proportion to its mass, and is involved principally in controlling body weight by suppressing appetite, stimulates the production of cytokines in the brain and may act as a new circulating messenger during disease. In addition to inhibiting appetite we also reported, for the first time, that leptin induces fever, which is a hallmark for disease and that leptin is integral to the body's defense mechanisms against bacterial infection and inflammation. Our latest discoveries indicate that the role of this cytokine like hormone in immunity is more complex than first envisaged and rather than acting directly on brain targets of inflammation it instead facilitates the action of other inflammatory molecules by regulating the state of readiness of the resident immune cells in the brain, namely microglia. We have discovered that the action of leptin on these cells makes them more likely to respond to an inflammatory stimulus efficiently. The work described in the current proposal will investigate this mechanism by posing the hypothesis that the role of leptin in immunity is that of a modulator of immune cell activity in the brain, which may include anti-apoptotic activity. 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 rodents to explore the underlying mechanisms responsible for the actions of leptin on microglial cells in the brain and in particular focus on the receptors involved and on how the fluctuation of circulating leptin levels can influence these effects.