The downregulation of CMKLR1 in Kupffer cells by a phosphatidyl inositol 3-kinase inhibitor improved hepatic insulin resistance and inflammation, suggesting that the chemerin–CMKLR1 signaling pathway contributes to metabolic disease in obesity by modulating the function of these immune cells [64]. This evidence concerns the gene RARRES2 and obesity due to melanocortin 4 receptor deficiency.