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Central role of the MC4R in appetite regulation following endotoxin

J.L. Sartin^*, D.L. Marks, C.D. McMahon^#, J.A. Daniel, P. Levasseur, C.G. Wagner^*, B.K. Whitlock^* and B.P. Steele^*

^* Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849 , Pediatric Endocrinology, Oregon Health & Science University, Portland OR 97239 , ^# AgResearch Ltd, Hamilton, NZ Animal Science, Berry College, Berry, GA 30149

sartijl{at}vetmed.auburn.edu

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 (LPS) on appetite. Sheep received an intracerebroventricular injection of either saline or AgRP (0.5 nmol/kg BW) 1h before intravenous injection of either saline or LPS (0.6 µg/kg BW) at time 0 and again at 4h. 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 there was an increase in the percent of AgRP neurons with c-Fos immunoreactive nuclei 6 h after sheep were injected with LPS (P < 0.04) and a corresponding decrease in -melanocyte stimulating hormone (-MSH) neurons co-expressing c-Fos (P < 0.001). In situ hybridization provided evidence for an increase in AgRP gene expression and a decrease in proopiomelanocortin gene expression 6h 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. Since AgRP inhibition of the MC4R prevents appetite inhibition in response to LPS and after LPS inhibition of feed intake both AgRP and -MSH 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.

Key Words: -melanocyte stimulating hormone • agouti related protein • food intake • hypothalamus • sheep • melanocortin-4 receptors