Aims/hypothesisInterleukin-6 is an inflammatory cytokine with pleiotropic effects upon nutrient homeostasis. Many reports show that circulating IL6 correlates with obesity and contributes to insulin resistance; however, IL6 can promote energy expenditure that improves glucose homeostasis.MethodsWe investigated nutrient homeostasis in C57BL/6J mice with sustained circulating human IL6 (hIL6) secreted predominantly from brain and lung (hIL6tg mice).ResultsThe hIL6tg mice displayed no features of systemic inflammation and were more insulin-sensitive than wild-type mice. On a high-fat diet, hIL6tg mice were lean, had low leptin concentrations, consumed less food and expended more energy than wild-type mice. Like ob/ob mice, the ob/obIL6 mice (generated by intercrossing ob/ob and hIL6tg mice) were obese and glucose-intolerant. However, low-dose leptin injections increased physical activity and reduced both body weight and food intake in ob/obIL6 mice, but was ineffective in ob/ob mice. Leptin increased hypothalamic signal transducer and activator of transcription-3 phosphorylation in ob/obIL6 mice, whereas ob/ob mice barely responded.Conclusions/interpretationHuman IL6 enhanced central leptin action in mice, promoting nutrient homeostasis and preventing diet-induced obesity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-009-1580-8) contains supplementary material, which is available to authorised users.