BACKGROUND: Plasma leptin levels decline in response to food restriction. We hypothesized that the magnitude of this decline would predict the amount of weight lost in response to exogenous leptin administration. METHODS: Thirty obese subjects were mildly energy-restricted for 21 days. Subsequently, they were randomized to receive either recombinant human leptin [rL, 10 mg s.c. once (n=15) or twice (n=6) daily] or placebo (n=9) as an adjunct to the dietary measures for 12 weeks. RESULTS: Weight loss amounted to 2.8+/-1.1, 5.2+/-0.9, and 7.9+/-1.4 kg (mean+/-standard error) (p=0.035 vs. placebo) in placebo, rL once daily, and rL b.i.d. treated subjects, respectively. The reduction in plasma leptin concentrations during the initial 21 days was positively correlated with the loss of body weight following leptin treatment (r(2)=0.24, p=0.04). Plasma leptin concentration prior to the initiation of rL therapy was inversely associated with the amount of body weight lost in response to intervention (r(2)=0.36, p=0.003). CONCLUSION: Leptin administration counteracts the adaptations that are actuated by the drop in leptin concentrations and thereby disrupts energy balance to promote weight loss.