Linking energy balance to systemic inflammation: role of leptin

Abstract

Systemic inflammation is invariably associated with a thermoregulatory response: fever or hypothermia. The mechanisms of the selection between these responses are virtually unknown. We propose that the adipocyte-derived hormone, leptin, links the energy status of a subject to the selection of an appropriate thermoregulatory response during systemic inflammation. Conscious rats will be injected with bacterial lipopolysaccharide at doses that activate both febrigenic signaling (mediates fever) and cryogenic signaling (mediates hypothermia). Manipulations of the thermal environment will be employed to distinguish febrigenic from cryogenic signaling, a strategy that is based on the fact that the body temperature of rats in a warm environment is influenced only by febrigenic signals, whereas the body temperature of rats in a cooler environment is subject to the effects of cryogenic signals as well. Such a strategy will be used in conjunction with measurements of inflammatory mediators with known febrigenic or cryogenic actions. We expect to show that leptin inhibits cryogenic signaling while having little or no impact on febrigenic signaling. Withdrawal of this inhibition in food-deprived rats, in which leptin production is low, is expected to favor the development of hypothermia over fever. We will also identify the site of the anti-cryogenic action of leptin, with emphasis on the dorsomedial hypothalamus. Last, but not least, we will test two possible mechanisms by means of which leptin could inhibit cryogenic signaling. The first mechanism involves the preferential inhibition of cryogenic signaling over febrigenic signaling by an overactivation of the hypothalamo-pituitary-adrenal axis. The second mechanism involves altered responsiveness of thermoregulatory neurons to cryogenic mediators. (AU)