ANOREXIA AND ADIPSIA - DISSOCIATION FROM FEVER AFTER MIP-1 INJECTION IN VENTROMEDIAL HYPOTHALAMUS AND PREOPTIC AREA OF RATS

Certain cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) act centrally to affect eating behavior and thermoregulation and may be involved in the physiological mechanisms leading to anorexia, adipsia and loss in body weight. The newly discovered macrophage inflammatory protein-1 (MIP-1) infused into the anterior hypothalamic, preoptic area (AH/POA) evokes an intense hyperthermia. The present experiments were designed to determine whether MIP-1 affects the feeding mechanism in the ventromedial hypothalamus (VMH) independently of the thermoregulatory mechanism in the AH/POA. For the microinjection of MIP-1, guide cannulae were implanted stereotaxically in the rat just above the VMH or AH/POA. Following postoperative recovery, each unrestrained rat was adapted to procedures whereby body temperature and intakes of food and water available ad lib were monitored at predetermined intervals. When an efficacious dose of 5.6 picograms (pg) MIP-1 was microinjected in a volume of 0.5-mu-l into the VMH, the intake of food in the rat was reduced significantly in the short term and throughout the following 22 h. Within intervals of 30 min and 4.0 h following MIP-1, the amount of food consumed was 4.0 and 10 g, respectively, below that eaten by control rats given the saline solvent vehicle injected at the same site in the VMH. Over the entire test period, the intake of water was similarly significantly below that of the control rats. Whereas MIP-1 injected into the AH/POA evoked fever accompanied by a transient decline in feeding, the body temperature of the rats was unaffected by the cytokine injected in the VMH. Thus, a functional dissociation between the AH/POA and VMH in terms of feeding responses to MIP-1 demonstrates that anorexia and adipsia following a cytokine challenge are independent of the febrile response. When either of these pathophysiological conditions arise, in conjunction with a cytokine-induced fever, it is likely that they may comprise secondary responses to the condition of an elevated body temperature. Finally, MIP-1 like other cytokines acts on neurons of the VMH, apparently on the glucoreceptor or related mechanism possibly mediated by catecholaminergic neurotransmitters.