BACKGROUND: The effects of food restriction on energy metabolism have been under investigation for more than a century. Data obtained are conflicting and research has failed to provide conclusive results. OBJECTIVE: The objective of this study was to test the hypothesis that in lean subjects under normal living conditions, short-term starvation leads to an increase in serum concentrations of catecholamines and thus to an increase in resting energy expenditure. DESIGN: Resting energy expenditure, measured by indirect calorimetry, and hormone and substrate concentrations were measured in 11 healthy, lean subjects on days 1, 2, 3, and 4 of an 84-h starvation period. RESULTS: Resting energy expenditure increased significantly from 3.97 +/- 0.9 kJ/min on day 1 to 4.53 +/- 0.9 kJ/min on day 3 (P < 0.05). The increase in resting energy expenditure was associated with an increase in the norepinephrine concentration from 1716. +/- 574 pmol/L on day 1 to 3728 +/- 1636 pmol/L on day 4 (P < 0.05). Serum glucose decreased from 4.9 +/- 0.5 to 3.5 +/- 0.5 mmol/L (P < 0.05), whereas insulin did not change significantly. CONCLUSIONS: Resting energy expenditure increases in early starvation, accompanied by an increase in plasma norepinephrine. This increase in norepinephrine seems to be due to a decline in serum glucose and may be the initial signal for metabolic changes in early starvation.