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Role of central melanocortins in endotoxin-induced anorexia
Q H Huang1, V J Hruby, J B Tatro
1Division 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, USA.
Abstract:
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 alpha-melanocyte stimulating hormone (alpha-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 micrograms/kg ip), followed 30 min later by intracerebroventricular injection of either alpha-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 alpha-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 alpha-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.
Insights
Melanocortins influence the acute phase response differently. While they reduce fever, both external and internal melanocortins contribute to reduced appetite and activity during inflammation.
Area of Science:
- Neuroendocrinology
- Immunology
- Physiology
Background:
- Inflammation and infection trigger symptoms like fever, anorexia, and hypoactivity, mediated by cytokines.
- Melanocortins centrally suppress fever but their role in anorexia and hypoactivity is unclear.
Purpose of the Study:
- To investigate the effects of alpha-melanocyte stimulating hormone (alpha-MSH) and melanocortin receptor antagonists on lipopolysaccharide (LPS)-induced anorexia and fever.
- To determine the roles of exogenous and endogenous melanocortins in the acute phase response.
Main Methods:
- Rats received intraperitoneal LPS injection, followed by intracerebroventricular administration of alpha-MSH or MC3-R/MC4-R antagonist SHU-9119.
- Food intake, locomotor activity, and body temperature were monitored over 24 hours.
Main Results:
- Exogenous alpha-MSH potentiated LPS-induced anorexia and hypoactivity, but alleviated fever at higher doses.
- Blocking central melanocortin receptors (MC3-R/MC4-R) with SHU-9119 reversed LPS-induced anorexia and enhanced fever.
- SHU-9119 did not affect LPS-induced suppression of locomotion.
Conclusions:
- Central melanocortins have divergent effects on the acute phase response.
- Melanocortins contribute to LPS-induced anorexia and hypoactivity.
- Melanocortins suppress LPS-induced fever.