A reappraisal on the ability of leptin to induce fever

Leptin is often regarded as a mediator of fever, even though an in-depth analysis of the dose-dependent effects of leptin on body temperature (Tb), pro-inflammatory cytokines, and circulating leptin has never been performed. In the present study, such an analysis was performed in rats that were food deprived (lower baseline levels of leptin) or free feeding (higher baseline levels of leptin). In a relatively cool environment (22 °C), rats deprived of food for 24 h exhibited mild (~ 0.5 °C) hypothermia. Leptin infusion (250 μg/kg iv) elevated the Tb of the food-deprived rats to a normothermic level, an effect that peaked (120 min post-infusion) when plasma leptin was at a level (~ 8 ng/mL) often found in leptin-responsive subjects. Increasing the leptin dose to 1000 μg/kg did not produce any further (febrile) elevation in the Tb of food-deprived rats. The anti-hypothermic effect of leptin in food-deprived rats was not associated with any rise in the plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6. In free-feeding rats kept in a cooler (22 °C) or warmer (28 °C) environment, leptin infusion failed to alter Tb or to produce any surge in plasma TNF-α or IL-6, even when the dose infused (3500 μg/kg iv) resulted in excessive, non-physiological rises in plasma leptin (~ 542 ng/mL at 30 min; ~ 75 ng/mL at 120 min post-infusion). In contrast, free-feeding rats in the same experimental set-up were able to respond to a low dose (2 μg/kg iv) of IL-1β with a typical biphasic fever, which was associated with surges in plasma TNF-α and IL-6. Collectively, our data show that an acute rise in plasma leptin to a level within or fairly above the physiological range does not induce fever. These results challenge the idea that leptin may be a mediator of fever.