BACKGROUND Leptin is thought to represent a peripheral signal involved in the regulation of energy balance. Its action has been studied in animals and obese subjects. Little is known about leptin's role during negative energy balance. OBJECTIVE The objective was to evaluate the relation between energy turnover, body composition, and plasma leptin concentrations in anorexia nervosa (AN). METHODS Sixteen weight-stable women with AN were compared with 22 control subjects and 14 rehabilitated AN patients (R-AN). Basal metabolic rate (BMR) was measured by indirect calorimetry; fat-free mass (FFM) and fat mass (FM) were calculated according to a 4-compartment model. Plasma leptin was determined by radioimmunoassay. RESULTS The BMR of AN patients (2.73 +/- 0.37 kJ/min) was significantly lower than that of control subjects (3.45 +/- 0.34 kJ/min) (P < 0.001), even after adjustment for FFM (2.92 +/- 0.33 kJ/min in AN patients and 3.30 +/- 0.26 kJ/min in control subjects; P < 0.004). Plasma leptin concentrations in AN patients were 76% lower than in control subjects, even after body fat was controlled for. In R-AN patients, BMR was not significantly different from that of control subjects and leptin concentrations were generally close to normal. Plasma leptin concentrations correlated significantly with FM (r(2) = 0.53, P < 0.0000) and BMR, even after adjustment for FFM (r(2) = 0.21, P < 0.0003). CONCLUSIONS BMR and plasma leptin concentrations are depressed in patients with AN; this is not explained by body-composition changes. The relation between leptin and BMR suggests that leptin plays a role in the energy sparing response to exposure to chronic energy deficiency. The return of BMR to normal and the significant increase in leptin concentrations in R-AN patients suggests a full reversibility of this adaptation mechanism.