Fever response in lean (Fa/-) and obese (fa/fa) Zucker rats and its lack to repeated injections of LPS

The thermal responses of Fa/- and fa/fa Zucker rats to injections of sterile saline and to four injections of 20 mu g/kg LPS al 3-day intervals were measured by means of radiotelemetry. In response to injections of saline, only the Fa/- rats developed a short stress-induced increase in abdominal temperature. Such a stress-induced rise of core temperature was also monitored in Fa/- rats after a change of the animals' cages. In response to the first injection of LPS, the Fa/- rats developed the same stress-induced rise in abdominal temperature as observed after injection of solvent followed by a biphasic fever, the first phase within 100 and 225 min, and the second phase within 240 and 480 min after LPS injection. In the fa/fa rats the stress-induced rise in body temperature and the first phase of LPS-induced fever were significantly suppressed, whereas the second phase of LPS-fever was identical in Fa/- and fa/fa rats. In response to further injections of LPS no febrile response was measurable at all; just the short stress-induced rise in abdominal temperature remained manifest in the Fa/- rats. When the first injection of 20 yg/kg LPS was followed by injections of 100 and 1000 mu g/kg LPS, a febrile response remained manifest, but the second phase of fever was attenuated in response to the repeated challenge with higher doses of LPS. The complete endotoxin tolerance observed in response to the second and further injections of 20 mu g/kg seems thus to be due to a strongly reduced sensitivity to LPS after its first administration. Because data from the literature indicate a reduced sympathetic outflow to brown adipose tissue of fa/fa rats in general and during fever in particular, we tried to determine the activity of the sympathetic nervous system by measurement of excreted amounts of noradrenaline. Attempts failed to determine noradrenaline excretion during fever in lean and in obese animals. The daily excretion of noradrenaline at an ambient temperature of 22 degrees C (basal values) was 53.8 +/- 4.7 nmol/kg in Fa/- and 25.9 +/- 3.4 nmol/kg in fa/fa rats. These values were increased by a cold exposure (5 degrees C) for 24 h to 123.1 +/- 12.4 nmol/kg in Fa/- rats (229% of the basal value) vs. just 48.7 +/- 2.5 nmol/kg in fa/fa rats (188% of the basal value). This small, but significantly larger rise of cold-stimulated noradrenaline excretion in Fa/- rats is indicative of a reduced sympathetic function in the fa/fa rats, but does not explain the lack of stress-induced rise in body temperature and of the first phase of LPS-induced fever in the obese animals.