Is Leptin A Key to Metabolic Inflammation in Trauma and Sepsis?
The objective of the study by Negrin et al. was to evaluate whether there was a dose-dependent therapeutic effect of exogenous leptin on mortality in a two-hit trauma and sepsis model and whether these effects were dependent on IL-6. The findings suggest that leptin administration reduces mortality in a murine model of trauma and sepsis. The authors also suggest that the reported effect is mediated by IL-6 and conclude that leptin may be considered a therapeutic agent for the prevention or treatment of sepsis post trauma. New pathways by which the immune system influences outcomes of trauma and sepsis and identifying potential therapeutics are important for critical care investigators. While the study provides some important mechanistic information on leptin and IL-6 in trauma and sepsis, some interesting but puzzling data still need to be explained.
The authors demonstrate that higher-dose leptin administration improved survival in wild-type mice but not in IL-6 knockout mice after trauma/sepsis. While there was a survival benefit with leptin treatment, leptin treatment did not affect the activity level in mice after trauma/sepsis. It is difficult to understand how there is a survival benefit without a difference in activity level between the groups. An explanation for these discrepant findings may relate to the method of measurement. Activity level was scored once per day, scoring only live animals. No score was given to dead mice. Therefore, the activity level score does not reflect the group as a whole it only reflects the survivors’ activity level score. The lack of difference in activity level could also be explained by differences in food intake. At the examination of the body weights of these groups, the leptin-treated mice had lower body weights on days 4 to 6 after trauma/sepsis. An explanation for the weight differences could relate to less food intake in the leptin-treated mice compared with vehicle since leptin is known to suppress appetite. However, this was not examined in this study. Less food intake leading to weight loss may cause a relative reduction in activity and be reflected in no difference between leptin and the vehicle-treated groups.
Another concern is the lack of a robust effect of leptin on systemic inflammation during trauma/sepsis. This could be explained by two experimental conditions: the time point of examination and the route of administration. For example, in a previous study, Siegl et al. (4) demonstrated that leptin reduces plasma cytokines at earlier time points after sepsis (6, 24, 48 h). In the current study by Negrin et al. leptin-treated trauma/sepsis mice had decreased plasma TNFα levels but non-statistically significant changes in other plasma cytokines and no effect on organ inflammation or function. These levels were obtained late in sepsis (4 days after cecal ligation and puncture). Furthermore, the authors state that there were varying individual cytokine values. It is possible that the route of administration and absorption of leptin in sepsis may have contributed to these varying effects. It is well known that the route of administration may affect the biologic function of medications.