AMP-activated protein kinase (AMPK) serves as a major regulator of energy homeostasis and is activated by different glucose-lowering agents. Indeed, AMPK has been identified as an attractive target for the development of innovative molecules to treat type 2 diabetes. In this issue of Diabetologia (doi: 10.1007/s00125-011-2366-3 ), Huang and co-workers report that arctigenin activates muscle uptake of glucose and inhibits hepatocyte gluconeogenesis and lipogenesis by reducing mitochondrial respiration and inducing AMPK activity. Importantly, it is reported that arctigenin improves glucose and lipid metabolism in ob/ob mice. Based on this evidence, Huang and co-workers suggest that arctigenin may represent a valuable lead compound for developing innovative glucose-lowering molecules. While these findings are not entirely novel and mechanistic investigations are needed, the results strongly support the concept that arctigenin deserves to be further considered because of its several potentially beneficial in vivo effects. In particular, the authors conclude that further mechanistic studies on arctigenin might provide novel insight and opportunities for selective modulation of subcutaneous and visceral fat mass.