Novel strategies are needed to reduce the obesity epidemic. One promising strategy is activation of brown adipose tissue (BAT), either via the brain or directly, which increases energy expenditure by combustion of fatty acids (FAs) into heat. The enzyme complex AMP-activated protein kinase (AMPK) is crucially involved in energy metabolism and is highly expressed in both brain and BAT, regulating thermogenesis. As a general rule, BAT activity and energy expenditure are increased either by suppression of AMPK activity in the brain, resulting in enhanced sympathetic outflow towards BAT, or by activation of AMPK in BAT. Targeting AMPK may thus hold therapeutic potential for the treatment of obesity and related disorders.