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Leptin, a molecular link between nutritional status, brain and inflammation

McGill University
Publication Date
  • Psychology - Physiological
  • Biology
  • Medicine


Leptin is an adipocyte-derived cytokine originally identified as an anti-obesity hormone but is implicated in other functions including immunity. The work described in this thesis addressed leptin’s role as a neuroimmune mediator during systemic inflammation and the physiological significance of this role. We first demonstrated that leptin stimulates the production of interleukin-1β, a critical pro-inflammatory cytokine, through action on brain-resident macrophages, microglia and endothelial cells known to play key roles in the brain’s innate inflammation. Moreover, leptin displayed atypical inflammatory effects, acting as an enhancer/modulator rather than a bona fide stimulator of brain inflammation. In subsequent studies, we addressed the leptin regulation of inflammation in a physiological context and examined whether malnutrition (which reduces basal leptin levels) attenuates the brain’s innate inflammatory response in a leptin-dependent manner. Food deprivation prior to induction of brain inflammation blunted the up-regulation of cytokines, chemokines and adhesion molecules, and the recruitment of neutrophils to the brain. Repletion of leptin during fasting reversed all the indices of neuroinflammation, demonstrating that leptin modulates the brain’s innate inflammation in relation to the host’s nutritional status. These studies were extended to examine the role of leptin in fever, an energy demanding response to inflammation. Food deprivation significantly attenuated fever, in part through a leptin-dependent mechanism, supporting a role for leptin in linking energy balance and fever. However, leptin regulation of fever was dissociated from the febrigenic inflammatory response, highlighting the complexity of leptin’s role which depends to some degree on the severity of the pathogenic stimulus. Leptin reversed the fever attenuation most likely by activating thermoregulatory functions in the fasted animals. In summary, this thesis demonstrated th

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