Background Obesity contributes to many common diseases, including cardiovascular and metabolic disorders such as diabetes, hypertension, and stroke. Leptin and ciliary neurotrophic factor (CNTF), two members of the cytokine family, play important roles in controlling food intake and body weight in rodents. Here, we used the hydrodynamics-based gene delivery technique to introduce leptin and CNTF expression plasmids, pCAGGS-leptin and pCAGGS-CNTF, into mice and to assess whether they could induce high expression of leptin or CNTF and reduce food intake and body weight in the mice. Methods Plasmid DNA (50 mug) in lactated Ringer's solution (0.1 ml/g body weight) was rapidly injected into the tail vein of 4-week-old male MCH-ICR mice. Results After a single injection, serum leptin peaked (at 32.0 +/- 3.1 ng/ml) 2 days after the injection, and serum CNTF peaked (at 22.0 +/- 0.8 mug/ml) 1 day after the injection. The high expression of either leptin or CNTF was sustained and dramatically reduced food intake (CNTF and leptin group vs. control group; 2.3 +/- 0.5 and 3.1 +/- 0.5 g/day vs. 4.8 +/- 0.6 g/day; p < 0.001) and body weight (3 weeks after the injection; CNTF and leptin group vs. control group; -19.5% and +3.3% vs. +33.3-47.5%; p < 0.001) in the mice, suggesting potent in vivo activities for these exogenously expressed proteins. Conclusions These results suggest that hydrodynamics-based gene delivery could have broad applications in the study of appetite regulation and metabolism. Copyright (C) 2003 John Wiley Sons, Ltd.