shu-9119 and Fever

Of the central nervous system receptors that could mediate the energy balance effects of leptin, those of the hypothalamic arcuate nucleus receive the greatest attention. Melanocortin receptors (MC-Rs) contribute to the feeding and energetic effects of hypothalamically delivered leptin. Energy balance effects of leptin are also mediated by extrahypothalamic neurons including the hindbrain nucleus tractus solitarius. Hindbrain leptin receptors play a role in leptin's anorectic effects, but their contribution to its energetic effects and their functional interaction with melanocortin systems within the hindbrain remains unexplored. Here rats implanted with telemetric devices for recording energetic/cardiovascular responses were examined to determine whether: 1) hindbrain (fourth ventricular) leptin receptor stimulation triggers energetic and cardiovascular effects, 2) these effects are altered by a 6-wk high-fat diet maintenance, and 3) hindbrain MC-Rs mediate the thermogenic, cardiovascular, and anorexic effects of hindbrain leptin delivery. Results show that hindbrain leptin receptor stimulation produced long-lasting (>6 h) increases in core temperature and heart rate and also decreased food intake and body weight. These responses were not altered by high-fat maintenance, in contrast to what has been reported for forebrain leptin delivery. Fourth ventricular pretreatment with MC-R antagonist SHU 9119 completely abolished the hyperthermia, anorexia, and body weight loss seen with hindbrain-directed leptin but had no effects of its own. These data highlight a role for hindbrain leptin receptors in the initiation of energetic and anorexic responses and show that MCRs are part of the downstream mediation of hindbrain leptin-induced energy balance effects, paralleling effects observed for hypothalamic leptin receptors.

Topics: Animals; Anorexia; Body Temperature; Body Weight; Dietary Fats; Eating; Energy Metabolism; Fever; Glucose Tolerance Test; Heart Rate; Injections; Leptin; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Sprague-Dawley; Receptors, Melanocortin; Rhombencephalon

The cytokine interleukin-1 (IL-1), which mediates many responses to infection and injury, induces anorexia and fever through direct actions in the central nervous system. The melanocortin neuropeptides, such as alpha melanocyte-stimulating hormone (alpha-MSH), reportedly antagonize many actions of IL-1, including fever and anorexia. However, it is unknown whether endogenous melanocortins modulate anorexia induced by IL-1. The objective of the present study was to establish the effect of endogenous melanocortins on IL-1-induced anorexia and fever in the rat. Intracerebroventricular (i.c.v.) injection of IL-1beta caused a significant reduction in food intake and body weight gain, and a rise in core body temperature in conscious rats. Coadministration of the melanocortin-3/4 receptor (MC3/4-R) antagonist, SHU9119, reversed IL-1beta-induced reductions in food intake and body weight, but did not affect the febrile response to IL-1beta. These data suggest IL-1beta may elicit its effects on food intake through the melanocortin system, predominantly via the MC3-R or MC4-R. In contrast, IL-1beta-induced fever does not appear to be mediated or modulated by MC3-R or MC4-R activity.

Topics: alpha-MSH; Animals; Anorexia; Appetite Depressants; Body Temperature; Brain; Eating; Fever; Injections, Intraventricular; Interleukin-1; Kinetics; Male; Melanocyte-Stimulating Hormones; Pyrogens; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin; Receptors, Melanocortin; Weight Loss

Systemically administered alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits endotoxin (lipopolysaccharide; LPS)- or interleukin (IL)-1-induced fever and adrenocortical activation, but the sites of these actions and the mechanisms involved are unknown. The aims of this study were, first, to determine whether melanocortin receptors (MCR) located within the central nervous system mediate the suppressive effects of peripherally administered alpha-MSH on LPS-induced fever and activation of the pituitary-adrenal axis and, second, to determine whether systemic alpha-MSH suppresses the LPS-induced rise in plasma IL-6 levels, potentially contributing to its antipyretic effect. Male rats received Escherichia coli LPS (25 microg/kg ip). Core body temperatures (Tb) were determined hourly by radiotelemetry (0-8 h), and blood was withdrawn via venous catheters for plasma hormone immunoassays (0-2 h) and IL-6 bioassay (0-8 h). alpha-MSH (100 microg/kg ip) completely prevented the onset of LPS-induced fever during the first 3-4 h after LPS and suppressed fever throughout the next 4 h but did not affect Tb in afebrile rats treated with intraperitoneal saline rather than LPS. Intraperitoneal alpha-MSH also suppressed the LPS-induced rise in plasma IL-6, ACTH, and corticosterone (CS) levels. Intracerebroventricular injection of SHU-9119, a potent melanocortin-4 receptor (MC4-R)/MC3-R antagonist, completely blocked the antipyretic effect of intraperitoneal alpha-MSH during the first 4 h after LPS but had no effect on alpha-MSH-induced suppression of LPS-stimulated plasma IL-6 and CS levels. Taken together, the results indicate that the antipyretic effect of peripherally administered alpha-MSH during the early phase of fever is mediated by MCR within the brain. In contrast, the inhibition of LPS-induced increases in plasma CS and IL-6 levels by intraperitoneal alpha-MSH appears to be mediated by a different mechanism(s), and these effects do not contribute to its antipyretic action.

Topics: Adrenocorticotropic Hormone; alpha-MSH; Animals; Body Temperature; Cerebral Ventricles; Corticosterone; Escherichia coli; Fever; Infusions, Parenteral; Injections, Intraperitoneal; Injections, Intraventricular; Interleukin-6; Lipopolysaccharides; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Receptors, Corticotropin; Receptors, Peptide