The central melanocortin system plays a key role in the regulation of food intake and energy homeostasis. We investigated whether genetic or pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in mice and rats with heart failure. Permanent ligation of the left coronary artery (myocardial infarction (MI)) or sham operation was performed in wild-type (WT) or melanocortin-4 receptor (MC4R) knockout mice. Eight weeks after surgery, WT-Sham mice had significant increases in lean body mass (LBM; P<0.05) and fat mass (P<0.05), whereas WT-MI did not gain significant amounts of LBM or fat mass. Resting basal metabolic rate (BMR) was significantly lower in WT-Sham mice compared to WT-MI mice (P<0.001). In contrast, both MC4-Sham and MC4-MI mice gained significant amounts of LBM (P<0.05) and fat mass (P<0.05) over the study period. There was no significant difference in the BMR between MC4-Sham and MC4-MI mice. In the second experiment, rats received aortic bands or sham operations, and after recovery received i.c.v. injections of either artificial cerebrospinal fluid (aCSF) or the melanocortin antagonist agouti-related protein (AGRP) for 2 weeks. Banded rats receiving AGRP gained significant amount of LBM (P<0.05) and fat mass (P<0.05) over the treatment period, whereas banded rats receiving aCSF did not gain significant amounts of LBM or fat mass. These results demonstrated that genetic and pharmacologic blockade of melanocortin signaling attenuated the metabolic manifestations of cardiac cachexia in murine and rat models of heart failure.

Ghrelin is an octanoylated 28 amino acid peptide predominantly secreted by the stomach, and has potent stimulatory effects on appetite. Several laboratories, including our own, have demonstrated that ghrelin levels fall in states of acute inflammation brought about by injection of bacterial lipopolysaccharide (LPS). We now demonstrate that the decrease in circulating ghrelin is not due to a decrease in ghrelin gene expression, but is instead likely to be due to an acute decrease in ghrelin secretion. Furthermore, we have found that the change in circulating ghrelin during acute inflammation required a prostaglandin second messenger, but did not require the synthesis of nitric oxide. Interestingly, i.v. injection of prostaglandin E₂ failed to decrease circulating ghrelin levels, whereas prostacyclin decreased circulating ghrelin to a similar extent as did LPS. We also provide anatomical evidence for the mechanism of the regulation of ghrelin by inflammation. We demonstrate that the type 1 interleukin-1β (IL-1β) receptor is expressed within the gastric mucosa, but is not expressed by ghrelin cells. The prostacyclin receptor was also expressed in the gastric mucosa, and the majority of ghrelin-producing cells were found to co-express this receptor. Mice with genetic deletion of the type 1 IL-1 receptor do not suppress circulating ghrelin levels with LPS administration. Collectively, these data support a model in which the mechanism of inflammation induced decreases in ghrelin are due to the action of IL-1β on cells within the gastric mucosa that in turn produce prostacyclin as a second messenger. These data provide further support for the potential role of ghrelin as a therapeutic agent in acute and chronic inflammatory diseases.