Liver macrophages, Kupffer cells, have been proposed to contribute to metabolic disease through secretion of inflammatory cytokines. We found that LMs produce insulin-like growth factor–binding protein 7 (IGFBP7), that directly regulates liver metabolism. IGFBP7 binds to the insulin receptor and induces lipogenesis and gluconeogenesis via activation of extracellular-signal-regulated kinase (ERK) signalling. We further show that IGFBP7 is subject to RNA editing at a higher frequency in insulin- resistant than in insulin-sensitive obese patients (90% versus 30%, respectively), resulting in an IGFBP7 isoform with potentially higher capacity to bind to the insulin receptor.

In addition, secretion of such factor by macrophages in obese individuals is evolutionarily conserved as immune cells of fruit flies fed hight fat diet produce the IGFBP7 homolog Imaginal morphogenesis protein Late 2 (IMPL2). Moreover, knockdown of macrophage-secreted ImpL2 improves the metabolic profile of obese flies.