Abstract Hypothalamic 5′-adenosine monophosphate-activated protein kinase (AMPK) senses intracellular metabolic stress, i.e., an increase in the cellular AMP:ATP ratio, and integrates diverse hormonal and nutritional signals to restore energy balance. Recent evidence suggests that different nutrients can modulate AMPK activity in the hypothalamus, thereby controlling weight gain through a leptin-independent mechanism. Understanding the mechanisms by which nutrients control hypothalamic AMPK activity is crucial to the development of effective nutritional interventions for the treatment of food intake-related disorders, such as anorexia and obesity. This article highlights the current evidence for the intricate relationship between nutrients and hypothalamic AMPK activity.