Hypothalamic neurons have the capacity to sense and alter their activity in response to fluctuations in local nutrient concentrations. Alterations in glucose, fatty acid and amino acid concentrations have all been demonstrated to affect neuronal excitability and/or intracellular signaling pathways. The degree to which such changes in nutrient availability have the capacity to modify energy balance varies across nutrient type. The underlying mechanisms through which various nutrients affect food intake and overall energy balance involve both specific and shared neuronal substrates.