The human cytokine interleukin (IL)-37 is an anti-inflammatory member of the IL-1 family of cytokines. Transgenic expression of IL-37 in mice protects them from diet-induced obesity and associated metabolic complications including dyslipidemia, inflammation and insulin resistance. The precise mechanism of action leading to these beneficial metabolic effects is not entirely known. Therefore, we aimed to assess in detail the effect of transgenic IL-37 expression on energy balance, including food intake and energy expenditure. Feeding homozygous IL-37 transgenic mice and wild-type (WT) control mice a high-fat diet (HFD; 45% kcal palm fat) for 6 weeks showed that IL-37 reduced body weight related to a marked decrease in food intake. Subsequent mechanistic studies in mice with heterozygous IL-37 expression versus WT littermates, fed the HFD for 18 weeks, confirmed that IL-37 reduces food intake, which led to a decrease in lean body mass, but did not reduce fat mass and plasma lipid levels or alterations in energy expenditure independent of lean body mass. Taken together, this suggests that IL-37 reduces lean body mass by reducing food intake.