Nutrient sensitive neurons (glucose and fatty acids, FA) are present in both the hypothalamus and the brainstem and play a key role in nervous control of energy homeostasis. Through neuronal output, especially the autonomic nervous system, it is now evidenced that FA may modulate food behaviour and both insulin secretion and action. For example, central administration of oleate inhibits both food intake and hepatic glucose production in rats. This suggests that a slight increase in plasma FA concentrations in the postprandial state might be detected by the central nervous system as a satiety signal. At cellular levels, subpopulations of FA-sensitive neurons (either excited or inhibited by FA) are now identified within the hypothalamus. However molecular effectors of FA effects remain unclear. They probably include ionic channels such as chloride or potassium. FA metabolism seems also required to induce neuronal response. Thus, FA per se or their metabolites modulate neuronal activity, as a mean of directly monitoring ongoing fuel availability by CNS nutrient-sensing neurons involved in the regulation of insulin secretion. Beside these physiological effects, FA overload or dysfunction of their metabolism could impair nervous control of energy homeostasis and contribute to development of obesity and/or type 2 diabetes in predisposed subjects.