Role of central melanocortins in endotoxin-induced anorexia

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 α-melanocyte stimulating hormone (α-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 α-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 α-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 α-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.

Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1β administration

“…The current results show that pretreatment with the melanocortin antagonist blocked this reduction in activity. Decreased activity in response to IL-1β is consistent with reports in the literature (Morgan et al, 2004;Wieczorek and Dunn, 2006) and a consistent response to peripheral immune activation (e.g., LPS (Huang et al, 1999)). It has been reported that nonselective blockade of melanocortin receptors with the drug SHU9119 did not ameliorate LPS-induced hypoactivity and had no effect on its own (Huang et al, 1999).…”

“…Decreased activity in response to IL-1β is consistent with reports in the literature (Morgan et al, 2004;Wieczorek and Dunn, 2006) and a consistent response to peripheral immune activation (e.g., LPS (Huang et al, 1999)). It has been reported that nonselective blockade of melanocortin receptors with the drug SHU9119 did not ameliorate LPS-induced hypoactivity and had no effect on its own (Huang et al, 1999). However, this study used different drugs (SH9119 and LPS) than the current study and a different experimental design (the SHU9119 was given 30 after LPS administration (as opposed to 15 min pretreatment in the current studies) and the injections were given in the early lights on period (as opposed to at the onset of lights off)), which likely contribute to the differing results.…”

“…We have shown previously that IL-1 given peripherally activates POMC expressing neurons, in both the arcuate proper, and in laterally contiguous aspects of the hypothalamus (Reyes and Sawchenko, 2002). Central administration of either mixed or selective MC3R or MC4R antagonists blocked the anorexia associated with IL-1 (Joppa et al, 2005;Lawrence and Rothwell, 2001), lipopolysaccharide (LPS) (Huang et al, 1999) or a prostate tumor (Wisse et al, 2001). Even more compelling, a MC4R selective antagonist attenuated the anorexia and enhanced the gain of lean body mass and fat in a mouse cancer model , implicating MC4R directly in cancer cachexia.…”

A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

“…Mc4r are involved in the anorexia associated with lipopolysaccaride and tumor-induced cachexia [20,25,27,35,36]. To determine if antagonism of Mc4r by PG932 can attenuate illness behavior, we assessed food intake and spontaneous physical activity of mice treated with LPS (Fig.…”

Novel Aspects of Glucocorticoids Actions on Energy Homeostasis and Hydromineral Balance

“…It has been already demonstrated that the activation of POMC neurons promotes the release of -melanocyte stimulating hormone ( -MSH), which, in turn, activates melanocortin 4 receptor (MC4R) (Cone, 2005). Melanocortin has been also implicated in the LPS-induced hypophagia, since the administration of exogenous -MSH intensified, whereas the antagonism of MC4R attenuated the inhibitory effect of LPS on food intake (Fan et al, 1997;Huang et al, 1999). Within this context, glucocorticoids appear as negative regulators of melanocortin signaling, since ADX was shown not only to reduce AgRP expression in the hypothalamus of wild type mice, but also to reverse obese phenotype and restore hypothalamic melanocortin tone to control levels in leptin-deficient ob/ob mice (Makimura et al, 2000).…”