Obesity is a worldwide epidemic.Promoting browning of white adipose tissue (WAT) contributes to increased energy expenditure and hence counteracts obesity.Here we show that cordycepin (Cpn),a natural derivative of adenosine,increases energy expenditure,inhibits weight gain,improves metabolic profile and glucose tolerance,decreases WAT mass and adipocyte size,and enhances cold tolerance in normal and high-fat diet-fed mice.Cpn markedly increases the surface temperature around the inguinal WAT and tus the inguinal fat browner.Further investigations show that Cpn induces the development of brown-like adipocytes in inguinal and,to a less degree,epididymal WAT depots.Cpn also increases the expression of uncoupling protein 1 (UCP1) and other thermogenic genes in WAT and 3T3-L1 differentiated adipocytes,in which AMP-activated protein kinase (AMPK) plays an important role.Our results provide novel insights into the function of Cpn in regulating energy balance,and suggest a potential utility of Cpn in the treatment of obesity.