Energy homeostasis is kept through a complex interplay of nutritional, neuronal and hormonal inputs that are integrated at the level of the central nervous system (CNS). A disruption of this regulation gives rise to life-threatening conditions that include obesity and type-2 diabetes, pathologies that are strongly linked epidemiologically and experimentally. The hypothalamus is a key integrator of nutrient-induced signals of hunger and satiety, crucial for processing information regarding energy stores and food availability. Much effort has been focused on the identification of hypothalamic pathways that control food intake but, until now, little attention has been given to a potential role for the hypothalamus in direct control of glucose homeostasis. Recent studies have cast a new light on the role of the CNS in regulating peripheral glucose via a hypothalamic lipid-sensing device that detects nutrient availability and relays, through the autonomic nervous system, a negative feedback signal on food intake, insulin sensitivity and insulin secretion. This review aims to summarize recent discoveries that highlight the brain as a potential target for anti-diabetic strategies.