The hypothalamus fulfills multiple functions, e.g., integration of food and water ingestion, various forms of social behavior and physiological neuroendocrine activities. Hypothalamic areas, particularly the ventromedial, lateral and paraventricular areas (VMH, LHA and PVN respectively), that contribute to the regulation of food intake are also involved in the regulation of blood glucose and plasma free fatty acid (FFA) levels. This regulation is controlled both directly via neural pathways and indirectly by hormones, e.g., insulin, glucagon, norepinephrine (NE) and epinephrine (E). A description is presented of the intrahypothalamic connections and the pathways between the hypothalamus and the motor areas of both the sympathetic system in the spinal cord (the intermediolateral column IML) and the parasympathetic system in the brainstem (the dorsal motornucleus of the vagus and the nucleus ambiguus). Noradrenergic stimulation of the LHA, VMH and PVN can alter blood glucose, plasma FFA and insulin levels independently of each other, e.g., noradrenergic stimulation of the VMH leads to an increase of insulin, glucose and FFA. Exercise induced increases of glucose are suppressed by α-adrenergic blockade of the LHA, VMH and PVN. Alpha-adrenergic blockade of the VMH during exercise causes an exaggerated increase of plasma FFA whereas α-blockade of both the LHA and PVN does not change the normal exercise induced increase of plasma FFA. The apparent contradiction that both adrenergic stimulation and adrenergic blockade of the VMH result in an increase in FFA may be explained by assuming postsynaptic α- and β-adrenergic receptors in the VMH controlling glucose and FFA release respectively and FFA release and presynaptic inhibitory α-adrenergic receptors. Many of these changes are mediated through the circulating catecholamines NE and E. This humoral mechanism may also contribute to the regulation of complex cardiovascular changes that occur in relation to sympathetic activation during energy expenditure such as exercise.