Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here we show that IL-1 family member ¿IL-37, recently characterized as an anti-inflammatory cytokine, ameliorates obesity-induced inflammation and insulin resistance. Mice transgenic for human ¿IL-37 (¿IL-37tg) exhibit reduced numbers of adipose tissue macrophages, increased circulating levels of ¿adiponectin and preserved ¿glucose tolerance and insulin sensitivity after 16 weeks of HFD. In vitro treatment of adipocytes with recombinant ¿IL-37 reduces adipogenesis and activates AMPK signalling. In humans, elevated steady-state ¿IL-37 adipose tissue mRNA levels are positively correlated with insulin sensitivity and a lower inflammatory status of the adipose tissue. These findings reveal ¿IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans, and suggest that ¿IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes.