A synthetic analogue (AOD9604) of the lipolytic domain of human growth hormone (hGH) has been studied for its metabolic actions in obese Zucker rats. Daily treatment with an oral dose of AOD9604 of 500 microg/kg body weight for 19 days reduced over 50% (15.8 +/- 0.6 vs. 35.6 +/- 0.8 g) body weight gain of the animals in comparison with the control. The adipose tissues of the AOD9604--treated animals were found to have an increase in lipolytic activity. In contrast to chronic treatment with intact hGH, chronic treatment with AOD9604 showed no adverse effect on insulin sensitivity of the animals, as demonstrated with euglycemic clamp techniques. The results in the present study suggest that the analogue of the hGH lipolytic domain may have the potential to be developed into an orally usable and safe therapeutic agent for obesity.