The Ay allele at the agouti Locus Enhances Sensitivity to Endotoxin-Induced Lethality in Mice
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In the course of investigations on anorexia during infection, I found that B6-Ay mice had significantly increased sensitivity to lipopolysaccharide (LPS)-induced lethality as compared with isogenic B6 mice. I also found that the sensitivity to the lethal effect of LPS dramatically increased in aged mice (age effect), both B6 and B6-Ay. However, the Ay effect of enhancing sensitivity to LPS-induced lethality was still significant, suggesting that the Ay effect is independent of age. In the absence of tumor necrosis factor α (TNFα), the Ay effect was still significant, suggesting that the Ay effect is independent of TNFα toxicity. A dose of LPS of 100 μg per mouse caused 15% lethality in B6, 65% in B6-Ay (significantly higher than B6), and 100 % in leptin-deficient B6-ob/ob (significantly higher than B6 and B6-Ay). The results support the hypothesis that endogenous leptin has a protective role against infection, and that a part of this leptin effect is mediated by α-melanocyte-stimulating hormone (αMSH). In contrast to the results of simple blockade at the melanocortin 4 receptor (MC4R), B6-Ay suffered more severe LPS-induced anorexia than did B6; therefore, the pathway involving MC4R is not absolutely required for the LPS-induced anorexia, and the presence of pathways involving other melanocortin receptor types was suggested. Because αMSH is suggested to be an endogenous anti-inflammatory peptide, and because melanocortin 1 receptor (MC1R) is expressed in various cutaneous cell types, the Ay effect might be caused via the pathway involving MC1R. Physiologic significance of αMSH-MC1R interaction in host defense against infection is discussed.