Liver macrophages regulate metabolism through non-inflammatory factors

It is currently debated as to whether liver macrophage (LM) activation from an anti-inflammatory to pro-inflammatory phenotype contributes to obesity-induced metabolic diseases. Here we report that LMs do not undergo a pro-inflammatory phenotype switch in obesity-induced insulin resistance in mice and humans. Remarkably, immune response related genes remained also unchanged in fly immune cells (haemocytes) upon high fat feeding. However, unbiased transcriptomic analyses revealed that LMs produce non-inflammatory factors, such as insulin like growth factor binding protein 7 (Igfbp7), that directly regulate liver metabolism. Using a unique method to manipulate gene expression only in LMs in vivo, we discovered that IGFBP7 specifically produced by LMs binds the insulin receptor and induces lipogenesis and gluconeogenesis, two major pathways increased in metabolic diseases. This study shows that macrophages could contribute to insulin resistance independently of their inflammatory status and that targeting non-inflammatory factors produced by macrophages might represent a better strategy than anti-inflammatory drugs to tackle metabolic diseases.