The AMP-activated protein kinase (AMPK) is a sensor of metabolic stress and a key mediator in preserving metabolic homeostasis both at the cellular and organism levels. AMPK activation is considered a targetable mechanism for diseases associated with metabolic perturbations, such as diabetes, obesity, fatty liver disease and cancer, among others. However, the regulators of AMPK that antagonize AMPK activators remain unknown, although they are critical to efficiently target AMPK activation for therapeutic purposes.