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1 Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Department of Medicine and the Tupper Research Institute, Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts 02111; and 2 Department of Chemistry, University of Arizona, Tucson, Arizona 85721
Inflammation and microbial infection
produce symptoms, including fever, anorexia, and hypoactivity, that are
thought to be mediated by endogenous proinflammatory cytokines.
Melanocortins are known to act centrally to suppress effects on fever
and other sequelae of proinflammatory cytokine actions in the central
nervous system, but the roles of melanocortins in anorexia and
hypoactivity occurring during the acute phase response are unknown. The
present study was designed to determine the effects of exogenous and
endogenous 
-melanocyte stimulating hormone (-MSH) on
lipopolysaccharide (LPS)-induced anorexia in relation to their effects
on fever. Rats were fasted overnight to promote feeding behavior, then
injected intraperitoneally with LPS (100 µg/kg ip), followed 30 min
later by intracerebroventricular injection of either
-MSH or the melanocortin receptor subtype 3/subtype 4 (MC3-R/MC4-R)
antagonist SHU-9119. Food intake, locomotor activity, and body
temperature (Tb) were monitored
during the ensuing 24-h period. Each of two intracerebroventricular doses of -MSH (30 and 300 ng) potentiated the suppressive effects of
LPS on food intake and locomotion, despite the fact that the higher
dose alleviated LPS-induced fever. In control rats that were not
treated with LPS, only the higher dose of -MSH significantly inhibited food intake, and Tb and
locomotor activity were unaffected. To assess the roles of endogenous
central melanocortins, LPS-treated rats received
intracerebroventricular SHU-9119 (200 ng). Central MC3-R/MC4-R blockade
did not affect Tb or food intake
in the absence of LPS treatment, but it reversed the LPS-induced
reduction in 24-h food intake and increased LPS-induced fever without
altering the LPS-induced suppression of locomotion. Taken together, the results suggest that exogenous and endogenous melanocortins acting centrally exert divergent influences on different aspects of the acute
phase response, suppressing LPS-induced fever but contributing to
LPS-induced anorexia and hypoactivity.
lipopolysaccharide; -melanocyte stimulating hormone; melanocortin receptor; rat; SHU-9119
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