Central role of the melanocortin-4 receptors in appetite regulation after endotoxin1

Abstract

Melanocortin-4 receptors (MC4R) are key factors in the depression of appetite during disease. This study was designed to determine the role of agouti-related protein (AgRP) in the effect of endotoxin (lipopolysaccharide, LPS) on appetite. Sheep received an intracerebroventricular injection of either saline or AgRP (0.5 nmol/kg of BW) 1 h before intravenous injection of either saline or LPS (0.6 microg/kg of BW) at time 0 and again at 4 h. Agouti-related protein prevented the reduction in feed intake due to LPS (P < 0.05). In a second experiment, AgRP gene expression was unaffected at 3 h and increased (P < 0.01) at 6 h after LPS. Immunohistochemical evidence indicated that there was an increase in the percentage of AgRP neurons with c-Fos immunoreactive nuclei 6 h after sheep were injected with LPS (P < 0.04) and a corresponding decrease in a-melanocyte-stimulating hormone neurons coexpressing c-Fos (P < 0.001). In situ hybridization provided evidence for an increase in AgRP gene expression and a decrease in proopiomelanocortin gene expression 6 h after LPS (P < 0.05). In a final experiment, physiological elevation of orexigenic agents by short-term fasting kept feed intake at the same level as controls, in spite of the presence of LPS, similar to the effects of AgRP in Exp. 1. The AgRP inhibition of the MC4R prevents appetite inhibition in response to LPS and well after LPS inhibition of feed intake, both AgRP and a-melanocyte-stimulating hormone may change in a pattern that favors appetite increases. These studies support the notion of the MC4R as a critical component of the mechanism for appetite suppression due to endotoxin.

Selected hormonal and neurotransmitter mechanisms regulating feed intake in sheep

“…The effect was present between 4 and 12 h, but unlike other animal models, the effect on feed intake did not persist to 24 h (Wagner et al, 2004). Examination of whether altered AgRP expression contributed to reduced feed intake after endotoxin injection determined that there were no changes in AgRP expression during the early phase of appetite suppression (Sartin et al, 2008). In another experiment, AgRP injected before endotoxin prevented the inhibition of appetite (Sartin et al, 2008) characteristic of endotoxin treatment.…”

“…In sheep, in situ hybridization studies clearly localize POMC to the ARC (Henry et al, 2000;Clarke et al, 2000;Lincoln et al, 2001;Adam et al, 2002). In addition, immunohistochemical evidence for a-MSH (product of the POMC gene) was likewise found in the ARC (Sartin et al, 2008). In one study, POMC gene expression in the ARC was found to be unaffected by a short-term (4-day) fast .…”

“…In one study, injection of a melanocortin agonist, MTII (which activates the same receptor as a-MSH), upregulated kisspeptin and LH release (Backholer et al, 2009). In another study, a-MSH immunohistochemistry indicated that with time after endotoxin injection and associated with prolonged reductions (6 h) in feed intake, there is a reduction in a-MSH staining and a reduction in dual labeling for c-Fos, suggesting that a-MSH neurons were not being activated under these circumstances (Sartin et al, 2008). This reduced expression of POMC and a-MSH neuron activation was accompanied by an increase in AgRP gene expression and c-Fos staining.…”

“…Examination of whether altered AgRP expression contributed to reduced feed intake after endotoxin injection determined that there were no changes in AgRP expression during the early phase of appetite suppression (Sartin et al, 2008). In another experiment, AgRP injected before endotoxin prevented the inhibition of appetite (Sartin et al, 2008) characteristic of endotoxin treatment. This suggests that MC4R is a major component of the mechanism for inhibition of feed intake in diseased ruminants and suggests a possible means of reversing the negative impact of disease on feeding and perhaps on subsequent body wasting associated with disease .…”

Dietary Protein Modifies the Effect of the MC4R Genotype on 2-Year Changes in Appetite and Food Craving: The POUNDS Lost Trial

“…The melanocortin-4 receptor (MC4R) 12 gene, which is primarily expressed in the brain (1), participates in complex neurohormonal pathways with reciprocal effects on energy intake and expenditure (2)(3)(4)(5), primarily through its regulatory effect on appetite and satiety (6). MC4R is also a key factor in regulating body adiposity (7).…”