The receptors of apolipoprotein AⅠ and sphingosine 1-phosphate, two main factors mediating the protective effects of high-density lipoprotein (HDL) on blood vessels, are located in adipose tissues. Also, the lipid transfer proteins which mediate HDL remodeling are highly expressed in adipose tissues, suggesting HDL may regulate adipocyte energy metabolism through its components. It is known HDL particles isolated from healthy subjects or recombinant HDLs activate AMP-activated protein kinase (AMPK) in adipocytes and inhibit the oxidation of fatty acids. Further, in vitro and in vivo experiments confirm that the active components in HDL may activate AMPK activity by their receptor pathway, which may contribute to the regulating effects of HDL on adipocyte energy metabolism. It will be expected that studies in the effect of HDL on adipocyte AMPK may provide a new therapeutic target for prevention and treatment of obesity caused by abnormal fat metabolism.