The metabolic effects of electrical stimulation of the hypothalamus were investigated using indirect calorimetry. Stimulation of either the ventromedial hypothalamic nucleus (VMH) or the lateral hypothalamic area (LH) increased both respiratory quotient (RQ) and energy expenditure (EE) in 23 lightly anesthetized rats. The use of a muscle relaxant to reduce motor activity and a regression analysis on the residual activity showed that the metabolic changes were independent of motor activity following LH stimulation. The increased RQ indicates that stimulation increased the dependence on carbohydrates as an energy substrate. The increased EE indicates that the LH modulates EE by mediating thermogensis. The interpretation of the metabolic changes in RQ and EE following VMH stimulation is complicated by the fact that there were significant relationships between residual activity and metabolic changes in the sedated rats with VMH electrodes. Together, these data suggest that the hypothalamus regulates body weight by controlling energy expenditure, as well as energy intake. At the same time, hypothalamic activity influences which substrate the rat uses for energy. © 1987.