Loss of the lipopolysaccharide receptor TLR4, for example, confers some protection from insulin resistance following a high-fat diet.40 In addition, M2 macrophages dominate in adipose tissue in lean mice, whereas M1 macrophages accumulate in adipose tissue during obesity and are thought to contribute to systemic insulin resistance.41 At the level of gene expression, there were some differences between the effect of metformin in hepatocytes and macrophages although IL-1β was suppressed in both cell types. Here, TLR4 is linked to obesity due to melanocortin 4 receptor deficiency.