Human IL6 enhances leptin action in mice

Aims/hypothesis Interleukin-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. Methods We investigated nutrient homeostasis in C57BL/6J mice with sustained circulating human IL6 (hIL6) secreted predominantly from brain and lung (hIL6 tg mice). Results The hIL6 tg mice displayed no features of systemic inflammation and were more insulin-sensitive than wild-type mice. On a high-fat diet, hIL6 tg mice were lean, had low leptin concentrations, consumed less food and expended more energy than wild-type mice. Like ob/ob mice, the ob/ob IL⁶ mice (generated by intercrossing ob/ob and hIL6 tg mice) were obese and glucose-intolerant. However, low-dose leptin injections increased physical activity and reduced both body weight and food intake in ob/ob IL⁶ mice, but was ineffective in ob/ob mice. Leptin increased hypothalamic signal transducer and activator of transcription-3 phosphorylation in ob/ob IL⁶ mice, whereas ob/ob mice barely responded. Conclusions/interpretation Human IL6 enhanced central leptin action in mice, promoting nutrient homeostasis and preventing diet-induced obesity.